research articles on behavioral genetics

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Behavioural genetics articles from across Nature Portfolio

Behavioural genetics is the interdisciplinary effort to establish causal links between genes and animal (including human) behavioural traits and neural mechanisms. Methods used include twin studies, quantitative trait mapping by linkage to allelic variants, transgenic animals and targeted gene disruption or silencing.

Latest Research and Reviews

Large-language models facilitate discovery of the molecular signatures regulating sleep and activity

The knowledge in the large language model (LLM), generative pre-trained transformer (GPT) 3.5, is elicited to facilitate the discovery of MRE11 in regulating sleep in the presence of conspecifics by a multi-object video tracking system.

• Liubin Zheng
• Luoying Zhang

The gene “ degrees of kevin bacon” ( dokb ) regulates a social network behaviour in Drosophila melanogaster

The structure of a social network is thought to be heritable in many animals, including humans. Here, Rooke and colleagues identify a gene, which they name “ degrees of kevin bacon ( dokb )”, that is expressed in the central nervous system of Drosophila melanogaster and regulates the structure of social networks.

• Rebecca Rooke
• Joshua J. Krupp
• Joel D. Levine

Exome-wide analysis implicates rare protein-altering variants in human handedness

Left-handedness is a common and partly heritable trait. Here, the authors perform a genome-wide screen for rare, protein-altering genetic variants associated with handedness in over 350,000 people, and implicate the tubulin gene TUBB4B .

• Dick Schijven
• Sourena Soheili-Nezhad
• Clyde Francks

Genetic similarity between relatives provides evidence on the presence and history of assortative mating

Non-random mating can complicate genetic studies, but implications hinge on its history in prior generations. Here, the authors use genetic similarity between relatives to investigate which traits show evidence of recent changes in mating behavior.

• Hans Fredrik Sunde
• Nikolai Haahjem Eftedal
• Fartein Ask Torvik

An analysis of the accuracy of retrospective birth location recall using sibling data

Many surveys ask participants to retrospectively record their location of birth. Here, the authors find misreporting in retrospective birth location data in UK Biobank using data from siblings, which can lead to bias in estimates of the impact of location-based exposures.

• Stephanie von Hinke
• Nicolai Vitt

Male manipulation impinges on social-dependent tumor suppression in Drosophila melanogaster females

• Perla Akiki
• Pierre Delamotte
• Jacques Montagne

News and Comment

Deciphering the genetic architecture of pain intensity

Chronic pain is common, with more than one in five adult Americans reporting having pain daily or on most days. A multi-ancestry genomic analysis in 598,339 military veterans in the USA identifies 125 genetic variants associated with pain intensity, highlights shared genetic risk with substance use and psychiatric disorders, and reveals enrichment in GABAergic neurons as a key molecular contributor to experiencing pain.

We need more-diverse biobanks to improve behavioural genetics

Biobanks have emerged as valuable resources for studying behavioural and social genomics, but are not representative of global populations. Thus, current research findings do not generalize, and exacerbate knowledge and health inequalities. We call on researchers, publishers and funders to address barriers to biobank diversity.

• Alicia R. Martin

Trait correlations in human couples

People tend to form partnerships with others who are similar to themselves. A new meta-analysis examines correlations between human mating partners, and finds correlations across nearly every trait studied. Education, social attitudes and substance use showed the highest correlations. Effect sizes differed between studies, suggesting potential cultural contingency.

• Yayouk E. Willems
• Laurel Raffington

Leveraging family relatedness to detect participation bias in genetic studies

Identifying the ways that a study sample is not representative is essential for maximizing the generalizability of findings to the population. A new method proposes discerning non-representativeness in large-scale genetic studies by comparing the genotypes of closely related participants.

• Mark J. Adams

Genes influence parental investment in their child from conception to writing a will

A study of 30,000 parents across 6 international cohorts reveals that parental genes are linked with the investments that parents make in their offspring, from adopting more healthy behaviours during pregnancy to leaving wealth to adult children. The findings suggest that parental alleles that are not transmitted can affect children through influencing the environments that parents create for their children over the course of their lives.

Creative use of biobank data enables exploration of longstanding questions about bias

Responses to survey questionnaires are a vital component of nearly all social and behavioural research. This study examined item nonresponse behaviour across 109 questionnaire items from 360,628 individuals in the UK Biobank using phenotypic and genetic data. These results were used to build an improved understanding of how item nonresponse might lead to bias in genetic studies in general.

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Celebrating a Century of Research in Behavioral Genetics

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• Published: 20 January 2023
• Volume 53 , pages 75–84, ( 2023 )

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A century after the first twin and adoption studies of behavior in the 1920s, this review looks back on the journey and celebrates milestones in behavioral genetic research. After a whistle-stop tour of early quantitative genetic research and the parallel journey of molecular genetics, the travelogue focuses on the last fifty years. Just as quantitative genetic discoveries were beginning to slow down in the 1990s, molecular genetics made it possible to assess DNA variation directly. From a rocky start with candidate gene association research, by 2005 the technological advance of DNA microarrays enabled genome-wide association studies, which have successfully identified some of the DNA variants that contribute to the ubiquitous heritability of behavioral traits. The ability to aggregate the effects of thousands of DNA variants in polygenic scores has created a DNA revolution in the behavioral sciences by making it possible to use DNA to predict individual differences in behavior from early in life.

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Introduction

Although the history of heredity and behavior can be traced back to ancient times (Loehlin 2009 ), the first human behavioral genetic research was reported in the 1920s, which applied quantitative genetic twin and adoption designs to assess genetic influence on newly developed measures of intelligence. The 1920s also marked the beginning of single-gene research that led to molecular genetics. The goal of this review is to outline 100 years of progress in quantitative genetic and molecular genetic research on behavior, a whistle-stop tour of a few of the major milestones in the journey. The review focuses on human research even though non-human animal research played a major role in the first 50 years (Maxson 2007 ). It uses intelligence as a focal example because intelligence was the target of much human research, even though a similar story could be told for other areas of behavioral genetics such as psychopathology.

The Two Worlds of Genetics

The most important development during this century of behavioral genetic research has been the synthesis of the two worlds of genetics, quantitative genetics and molecular genetics. Quantitative genetics and molecular genetics both have their origins in the 1860s with Francis Galton (Galton 1865 , 1869 ) and Gregor Mendel (Mendel 1866 ), respectively. Not much happened until the 1900s when Galton’s insights led to methods to study genetic influence on complex traits and when Mendel’s work was re-discovered. The two worlds clashed as Mendelians looked for 3:1 segregation ratios indicative of single-gene traits, whereas Galtonians assumed that Mendel’s laws of heredity were specific to pea plants because they knew that complex traits are distributed continuously.

Antipathy between the two worlds of genetics followed because of the different goals of Mendelians and Galtonians. Mendelians, the predecessors of molecular geneticists, wanted to understand how genes work, which led to the use of induced mutations and a focus on dichotomous traits that were easily assessed such as physical characteristics rather than behavioral traits. In contrast, Galtonians, whose descendants are quantitative geneticists, used genetics as a tool to understand the etiology of naturally occurring variation in complex traits selected for their intrinsic interest and importance, with behavioral traits, especially intelligence, high on the list. The resolution to the conflict could be seen in Ronald Fisher’s 1918 paper, which showed that Mendelian inheritance is compatible with quantitative traits if the assumption is made that several genes affect a trait (Fisher 1918 ). Nonetheless, the two worlds of genetics went their own way for most of the century.

The synthesis of the two worlds of genetics began in the 1980s with the technological advances of DNA sequencing, polymerase chain reaction, and DNA microarrays that enabled genome-wide association (GWA) studies of complex traits. In addition to finding DNA variants associated with complex traits, GWA genotypes led to three far-reaching advances in genetic research. First, GWA genotypes were used to estimate directly the classical quantitative genetic parameters of heritability and genetic correlation, which could be called quantitative genomics . Second, the results of GWA studies were used to create polygenic scores that predict individual differences for complex traits. Third, GWA genotypes facilitated new approaches to causal modeling of the interplay between genes and environment. Together, when applied to behavioral traits, these advances could be called behavioral genomics . This synthesis of the two worlds of genetics, the journey from behavioral genetics to behavioral genomics, is the overarching theme of this whistle-stop tour celebrating a century of research in behavioral genetics. (See Fig.  1 .) The itinerary begins with milestones in quantitative genetics and then molecular genetics, concluding with behavioral genomics.

Synthesis of the two worlds of genetics: from behavioral genetics to behavioral genomics.

Quantitative Genetics

The first 50 years of quantitative genetic research, from 1920 to 1970, started off well with family studies (Jones 1928 ; Thorndike 1928 ), twin studies (Holzinger 1929 ; Lauterbach 1925 ; Merriman 1924 ; Tallman 1928 ) and adoption studies (Burks 1928 ; Freeman et al. 1928 ) using the recently devised IQ test. However, this nascent research was squelched with the emergence of Nazi eugenic policies (McGue 2008 ). The void was filled with behaviorism (Watson 1930 ), which led to environmentalism, the ‘blank slate’ view that we are what we learn (Pinker 2003 ).

Nonetheless, a few studies of IQ appeared in the 1930 and 1940 s, such as the first study of identical twins reared apart (Newman et al. 1937 ) and the first adoption study that assessed birth parents (Skodak and Skeels 1949 ). Both indicated substantial genetic influence on IQ, as did a review of all available IQ data (Woodworth 1941 ).

In 1960, the field-defining book, Behavior Genetics (Fuller and Thompson 1960 ), was published. It mostly reviewed research on nonhuman animals. In their preface, the authors noted that “we considered omitting human studies completely” (p. vi); even their chapter on cognitive abilities primarily reviewed nonhuman research. An earlier influential review began by saying, “In the writer’s opinion, the genetics of behavior must be worked out on species that can be subjected to controlled breeding. At the present time this precludes human subjects” (Hall 1951 ).

In 1963, a milestone review was published in Science of 52 family, twin and adoption studies of IQ (Erlenmeyer-Kimling and Jarvik 1963 ). Although the studies were very small by modern standards and heritability was not calculated, the average results from the different designs suggested substantial heritability. For example, the average MZ and DZ twin correlations were 0.87 and 0.53, respectively, suggesting a heritability of 68%. However, despite being published in Science , the paper was largely ignored; it was cited only 22 times in five years.

The pace of behavioral genetic research picked up in the 1960s, once again primarily research on non-human animals (Lindzey et al. 1971 ; McClearn 1971 ), although some twin studies on cognitive abilities were also published (Nichols 1965 ; Schoenfeldt 1968 ). However, the first 50 years of quantitative genetic research ended badly with the publication in 1969 of Arthur Jensen’s paper, How Much Can We Boost IQ and Scholastic Achievement? (Jensen 1969 ). The paper touched on ethnic differences, which made it one of the most controversial papers in the behavioral sciences, with 900 citations in the first five years and more than 6200 citations in total.

1970 was a watershed year marking the second 50 years of behavioral genetic research. It was the year that the Behavior Genetics Association was launched and the first issue of its journal, Behavior Genetics , was published. Another 1970 milestone was the publication of the foundational paper for model-fitting analysis of quantitative genetic designs (Jinks and Fulker 1970 ).

The 1970s and 1980s yielded most of the major discoveries for quantitative genetics as applied to behavioral traits, discoveries that are listed as landmarks in the following paragraphs. Nonetheless, in the aftermath of Jensen’s 1969 paper, behavioral genetic research, especially on intelligence, was highly controversial (Scarr and Carter-Saltzman 1982 ). Most notably, Leon Kamin severely criticized the politics as well as science of behavioral genetic research on intelligence in his book, The Science and Politics of I.Q. (Kamin 1974 ). He concluded that “There exist no data which should lead a prudent man to accept the hypothesis that I.Q. test scores are in any degree heritable” (p. 1). The book was cited more than 2000 times and stoked antipathy towards genetic research. It also impugned the motivation of genetic researchers, saying that they are ‘committed to the view that those on the bottom are genetically inferior victims of their own immutable defects’ (p. 2).

All Traits are Heritable

Despite this hostility, genetic research grew exponentially in the 1970s and created a seismic shift from the prevailing view that behavioral traits like intelligence are not “in any degree heritable”. In 1978, a review of 30 twin studies of intelligence yielded an average heritability estimate of 46% (Nichols 1978 ). Moreover, the conclusion began to emerge that all traits show substantial heritability. This conclusion, which has been called the first law of behavioral genetics (Turkheimer 2000 ), was first observed in 1976 in a twin study of cognitive data for 3000 twin pairs, which also included extensive data on personality and interests for 850 twin pairs (Loehlin and Nichols 1976 ). The authors noted “the curious uniformity of identical-fraternal differences both within and across trait domains” (p. 89). A 2015 meta-analysis of all published twin studies showed that behavioral traits are about 50% heritable on average (Polderman et al. 2015 ). Demonstrating the ubiquitous importance of genetics was the fundamental accomplishment of behavioral genetics.

No Traits are 100% Heritable

The flip side of the finding of 50% heritability was just as important: no traits are 100% heritable. It is ironic that, after a century of environmentalism, genetic research provided the strongest evidence for the importance of the environment; previous environmental research was confounded because it ignored genetics. Moreover, investigating environmental influences in genetically sensitive designs led to two of the most important discoveries about the environment: nonshared environment and the nature of nurture.

Nonshared Environment

Quantitative genetic research showed that environmental influences work very differently from the way they were assumed to work. A second discovery by Loehlin and Nichols ( 1976 ) was that salient environmental influences are not shared by twins growing up in the same family: “Environment carries substantial weight in determining personality – it appears to account for at least half the variance – but that environment is one for which twin pairs are correlated close to zero” (p. 92). This phenomenon has come to be known as nonshared environment (Plomin and Daniels 1987 ).

Loehlin and Nichols suggested that cognitive abilities are an exception to the rule that environmental influences make children in a family different from, not similar to, one another. Their twin study suggested that about 25% of the variance of cognitive abilities could be attributed to shared environment. A direct test of shared environmental influence is the correlation between adoptive siblings, genetically unrelated children adopted into the same family. Seven small studies of adoptive siblings yielded an average IQ correlation of 0.25, which seemed to precisely confirm the twin estimate (McGue et al. 1993 ).

However, in 1978, a study of 100 pairs of adoptive siblings reported an IQ correlation of -0.03 (Scarr and Weinberg 1978 ). This is a good example of the progressive nature of behavioral genetic research (Urbach 1974 ). Scarr and Weinberg noted that previous studies involved children, whereas theirs was the first study of post-adolescent adoptive siblings aged 16 to 22, and they hypothesized that the effect of shared environmental influence on cognitive development diminishes after adolescence as young adults make their own way in the world. Their hypothesis was confirmed in two additional studies of post-adolescent adoptive siblings that yielded an average IQ correlation of -0.01 (McGue et al. 1993 ). Evidence that shared environmental influence declines after adolescence to negligible levels for cognitive abilities has also emerged from twin studies (Briley and Tucker-Drob 2013 ; Haworth et al. 2010 ). However, one of the biggest mysteries about nonshared environment remains: what are these environmental influences that make children growing up in the same family so different (Plomin 2011 )?

The Nature of Nurture

Another milestone was the revelation that environmental measures widely used in the behavioral sciences, such as parenting, social support, and life events, show genetic influence (Plomin and Bergeman 1991 ), with heritabilities of about 25% on average (Kendler and Baker 2007 ). This finding emerged in the 1980s as measures of the environment were included in quantitative genetic designs, which also led to the discovery that associations between environmental measures and psychological traits are significantly mediated genetically (Plomin et al. 1985 ). The nature of nurture is one of the major directions for research in behavioral genomics, as discussed later.

Heritability Increases During Development

Another milestone in the 1970s was the Louisville Twin Study in which mental development of 500 pairs of twins was assessed longitudinally and showed that the heritability of intelligence increases from infancy to adolescence (Wilson 1983 ). In light of the replication crisis in science (Ritchie 2021 ), a cause for celebration is that this counterintuitive finding of increasing heritability of intelligence – from about 40% in childhood to more than 60% in adulthood -- has consistently replicated, as seen in cross-sectional (Haworth et al. 2010 ) and longitudinal (Briley and Tucker-Drob 2013 ) mega-analyses.

In 1977, a landmark paper showed how univariate analysis of variance can be extended to multivariate analysis of covariance in a model-fitting framework (Martin and Eaves 1977 ). They applied their approach to cognitive abilities and found an average genetic correlation of 0.52, indicating that many genes affect diverse traits, called pleiotropy . Subsequent studies also yielded genetic correlations greater than 0.50 between diverse cognitive abilities (Plomin and Kovas 2005 ).

In the 1970s and 1980s, bigger and better studies made most of the major quantitative genetic discoveries, going far beyond merely estimating heritability. But it was not all smooth sailing. Most notably, The Bell Curve resurrected many of the issues that followed Jensen’s 1969 paper (Herrnstein and Murray 1996 ). Nonetheless, by the 1990s, quantitative genetic research had convinced most scientists of the importance of genetics for behavioral traits, including intelligence (Snyderman and Rothman 1990 ). One symbol of this change was that the 1992 Centennial Conference of the American Psychological Association chose behavioral genetics as one of two themes that best represented the past, present, and future of psychology (Plomin and McClearn 1993 ). Then, just as quantitative genetic discoveries began to slow, the synthesis with molecular genetics began, which led to the DNA revolution and behavioral genomics.

Molecular Genetics

During its first 50 years, molecular genetics focused on single-gene disorders. In 1933, a Nobel prize was awarded to Thomas Hunt Morgan for mapping genes responsible for single-gene mutations in fruit flies (Morgan et al. 1923 ), but human mapping was stymied because only a few single-gene markers such as blood types were available – variants in DNA itself were not available for another fifty years. Research on single-gene effects discovered in pedigree studies only incidentally involved behavioral traits. For example, phenylketonuria, the most common single-gene metabolic disorder, was discovered in 1934 (Folling 1934 ) and shown to be responsible for 1% of the population institutionalized for severe intellectual disability.

In the 1940s, it became clear that DNA is the mechanism of heredity, culminating in the most famous paper in biology which proposed the double-helix structure of DNA (Watson and Crick 1953 ). An important milestone for human behavioral genetics was the discovery in 1959 that the most common form of intellectual disability, Down syndrome, was due to a trisomy of chromosome 21 (Lejeune et al. 1959 ).

In 1961, the genetic code was cracked showing that three-letter sequences of the four-letter alphabet of DNA coded for the 20 amino acids (Crick et al. 1961 ). Just as with quantitative genetics, the 1970s was a watershed decade that ushered in the second 50 years, the genomics era.

The Genomics Era

The era of genomics began in the 1970s when methods were developed to sequence DNA’s nucleotide bases (Sanger et al. 1977 ). In 2003, fifty years after the discovery of the double helix structure of DNA, the Human Genome Project identified the sequence of 92% of the three billion nucleotide bases in the human genome (Collins et al. 2003 ).

In the 1980s, the first common variants in DNA itself were discovered, restriction fragment length polymorphisms (RFLPs) (Botstein et al. 1980 ). RFLPs enabled linkage mapping for single-gene disorders and were the basis for DNA fingerprinting, which revolutionized forensics (Jeffreys 1987 ). Polymerase chain reaction (PCR) was also developed which facilitated genotyping by rapidly amplifying DNA fragments (Mullis et al. 1986 ). In the 1980s, these developments increased the pace of linkage mapping of single-gene disorders, many of which had cognitive consequences, such as phenylketonuria (Woo et al. 1983 ) and Huntington disease (Gusella et al. 1983 ). In the 1990s, DNA sequencing revealed thousands of single-nucleotide polymorphisms (SNPs), the most common DNA variant (Collins et al. 1997 ).

In the 1990s, linkage was also attempted for complex traits that did not show single-gene patterns of transmission, such as reading disability (Cardon et al. 1994 ), but these were unsuccessful because linkage, which traces chromosomal recombination between disease genes and DNA variants within families, is unable to detect small effect sizes (Plomin et al. 1994 ). Researchers then pivoted towards allelic association in unrelated individuals, which is much more powerful in detecting DNA variants of small effect size. An early example of association was an allele of the apolipoprotein E gene on chromosome 19 that was found in 40% of individuals with late-onset Alzheimer disease as compared to 15% in controls (Corder et al. 1993 ).

The downside of allelic association is that an association can only be detected if a DNA variant is itself the functional gene or very close to it. For this reason, and because genotyping each DNA variant was slow and expensive, the 1990s became the decade of candidate gene studies in which thousands of studies reported associations between complex behavioral traits and a few ‘candidate’ genes, typically neurotransmitter genes thought to be involved in behavioral pathways. However, these candidate-gene associations failed to replicate because these studies committed most of the sins responsible for the replication crisis (Ioannidis 2005 ). For example, when 12 candidate genes reported to be associated with intelligence were tested in three large samples, none replicated (Chabris et al. 2012 ).

Genome-wide Association

In 1996, an idea emerged that was the opposite of the candidate-gene approach: using thousands of DNA variants to systematically assess associations across the genome in large samples of unrelated individuals (Risch and Merikangas 1996 ). However, genome-wide association (GWA) seemed a dream because genotyping was slow and expensive.

The problem of genotyping each DNA variant in large samples was solved in the 2000s by the commercial availability of DNA microarrays, called SNP chips , which genotype hundreds of thousands of SNPs for an individual quickly, accurately, and inexpensively. SNP chips paved the way for GWA analyses. In 2007, the first major GWA analysis included 2000 cases for each of seven major disorders and compared SNP allele frequencies for these cases with controls (The Wellcome Trust Case Control Consortium 2007 ). Replicable associations were found but they were few in number and extremely small in effect size. Hundreds of GWA reports appeared in the next decade with similarly small effect sizes across the behavioral and biological sciences (Visscher et al. 2017 ), including cognitive traits such as educational attainment (Rietveld et al. 2013 ) and intelligence in childhood (Benyamin et al. 2014 ) and adulthood (Davies et al. 2011 ).

These GWA studies led to the realization that the biggest effect sizes were much smaller than anyone anticipated. For case-control studies, risk ratios were less than 1.1, and for dimensional traits, variance explained was less than 0.001. This meant that huge sample sizes would be needed to detect these miniscule effects, and thousands of these associations would be needed to account for heritability, which is usually greater than 50% for cognitive traits. Ever larger GWA samples scooped up more of these tiny effects. Most recently, a GWA meta-analysis with a sample size of 3 million netted nearly four thousand independent significant associations after correction for multiple testing, but the median effect size of these SNPs accounted for less than 0.0001 of the variance (Okbay et al. 2022 ).

A century after Fisher’s 1918 paper, the discovery of such extreme polygenicity (Boyle et al. 2017 ; Visscher et al. 2021 ) was a turning point in the voyage from behavioral genetics to behavioral genomics. GWA genotypes brought the two worlds of genetics together by making it possible to use GWA genotypes to create three sets of tools to investigate highly polygenic traits: quantitative genomics, polygenic scores, and causal modeling (see Fig.  1 ). When applied to behavioral traits, these tools constitute the new field of behavioral genomics.

Quantitative Genomics

What good are SNP associations that account for such tiny effects? The molecular genetic goal of tracking effects from genes to brain to behavior is daunting when the effects are so small. However, in contrast to this bottom-up approach from genes to behavior, the top-down perspective of behavioral genetics answered this question by using GWA genotypes to estimate quantitative genetic parameters of heritability and genetic correlations, which could be called quantitative genomics . The journey picked up speed as quantitative genomics led to three new milestones.

Genome-wide Complex Trait Analysis (GCTA). In 2011, the first new method was devised to estimate heritability and genetic correlations since twin and adoption designs in the early 1900s. GCTA (originally called GREML) uses GWA genotypes for large samples of unrelated individuals to compare overall SNP similarity to phenotypic similarity pair by pair for all pairs of individuals (Yang et al. 2011 ). The extent to which SNP similarity explains trait similarity is called SNP heritability because it is limited to heritability estimated by the SNPs on the SNP chip. Genetic correlations are estimated by comparing each pair’s SNP similarity to their cross-trait phenotypic similarity.

SNP heritability estimates are about half the heritability estimated by twin studies (Plomin and von Stumm 2018 ). This ‘missing heritability’ occurs because SNP heritability is limited to the common SNPs genotyped on current SNP chips, which also creates a ceiling for discovery in GWA research. Most SNPs are not common, and rare SNPs appear to be responsible for much of the missing heritability, at least for height (Wainschtein et al. 2022 ). Importantly, quantitative genomic estimates of genetic correlations are not limited in this way and thus provide estimates of genetic correlations similar to those from twin studies (Trzaskowski et al. 2013 ).

Linkage Disequilibrium Score (LDSC) Regression. In 2015, a second quantitative genomic method, LDSC, was published which estimates heritability and genetic correlations from GWA summary effect size statistics for each SNP, corrected for linkage disequilibrium between SNPs (Bulik-Sullivan et al. 2015 ). LDSC estimates of heritability and genetic correlations are similar to GCTA estimates, although GCTA estimates are generally more accurate (Evans et al. 2018 ; Ni et al. 2018 ). The advantage of LDSC is that it can be applied to published GWA summary statistics in contrast to GCTA which requires access to GWA data for individuals in the GWA study.

Genomic Structural Equation Modeling (Genomic SEM). In 2019, a third quantitative genomic analysis completed the arc from quantitative genetics to quantitative genomics by combining quantitative genetic structural equation model-fitting, routinely used in twin analyses, to LDSC heritabilities and genetic correlations (Grotzinger et al. 2019 ). Genomic SEM provides insights into the multivariate genetic architecture of cognitive traits (Grotzinger et al. 2019 ) and psychopathology (Grotzinger et al. 2022 ).

The second answer to the question about what to do with SNP associations that have such small effect sizes is the creation of polygenic scores.

Polygenic Scores

A milestone that marks the spot where the DNA revolution began to transform the behavioral sciences is polygenic scores. Rather than using GWA genotypes to estimate SNP heritabilities and genetic correlations, polygenic scores use GWA genotypes to create a single score for each individual that aggregates, across all SNPs on a SNP chip, an individual’s genotype for each SNP (0, 1 or 2) weighted by the SNP’s effect size on the target trait as indicated by GWA summary statistics. In 2001, polygenic scores were introduced in plant and animal breeding (Meuwissen et al. 2001 ) and later in cognitive abilities (Harlaar et al. 2005 ) and psychopathology (Purcell et al. 2009 ). GWA summary statistics needed to create polygenic scores are now publicly available for more than 500 traits, including dozens for psychiatric disorders and other behavioral traits including cognitive traits (PGS Catalog 2022 ).

The most predictive polygenic scores in the behavioral sciences are for cognitive traits, especially educational attainment and intelligence. Early GWA studies of cognitive traits were underpowered to detect the small effects that we now know are responsible for heritability (Plomin and von Stumm 2018 ). In 2013, a landmark was a GWA study of educational attainment with a sample size exceeding 100,000 (Rietveld et al. 2013 ). A polygenic score derived from its GWA summary statistics predicted 2% of the variance of educational attainment in independent samples. The finding that the biggest effects accounted for only 0.0002 of the variance of educational attainment made it clear that much larger samples would be needed to scoop up more of the tiny effects responsible for the twin heritability estimate of about 40%. In the past decade, the predictive power of polygenic scores for educational attainment has increased with increasing sample sizes from 2% (Rietveld et al. 2013 ) to 5% (Okbay et al. 2016 ) to 10% (Lee et al. 2018 ) to 14% in a GWA study with a sample size of three million (Okbay et al. 2022 ). The current polygenic score for intelligence, derived from a GWA study with a sample of 280,000, predicted 4% of the variance (Savage et al. 2018 ), but, together, the polygenic scores for educational attainment and intelligence predicted 10% of the variance of intelligence test scores (Allegrini et al. 2019 ).

The next milestone will be to narrow the gap between heritability explained by polygenic scores and SNP heritability. A more daunting challenge will be to break through the ceiling of SNP heritability to reach the heritability estimated by twin studies. Reaching both of these destinations will be facilitated by even larger GWA studies and whole-genome sequencing (Wainschtein et al. 2022 ).

Polygenic scores are unique predictors because inherited DNA variations do not change systematically during life – there is no backward causation in the sense that nothing in the brain, behavior or environment changes inherited differences in DNA sequence. For this reason, polygenic scores can predict behavioral traits from early in life without knowing anything about the intervening pathways between genes, brain, and behavior.

Polygenic scores have brought behavioral genetics to the forefront of research in many areas of the life sciences because polygenic scores can be created in any sample of unrelated individuals for whom GWA genotype data are available. No special samples of twins or adoptees are needed, nor is it necessary to assess behavioral traits in order to use polygenic scores to predict them.

Although the implications and applications of polygenic scores derive from its power to predict behavioral traits without regard to explanation (Plomin and von Stumm 2022 ), another milestone on the road to behavioral genomics has been the leverage provided by GWA genotypes for causal modeling.

Causal Modeling

A final milestone on the journey from behavioral genetics to behavioral genomics is a suite of new approaches that use GWA genotypes in causal models that attempt to dissect sources of genetic influence on behavioral traits (Pingault et al. 2018 ). Although traditional quantitative genetic models are causal models, GWA genotypes have enhanced causal modeling in research on assortative mating (Border et al. 2021 ; Yengo et al. 2018 ), population stratification (Abdellaoui et al. 2022 ; Lawson et al. 2020 ), and Mendelian randomization (Richmond and Davey Smith 2022 ).

An explosion of research on genotype-environment correlation was ignited by a 2018 paper in Science on the topic of the nature of nurture (Kong et al. 2018 ). The study included both parent and offspring GWA genotypes and showed that a polygenic score computed from non-transmitted alleles from parent to offspring influenced offspring educational attainment; these indirect effects were dubbed genetic nurture . GCTA has also been used to investigate genotype-environment correlation (Eilertsen et al. 2021 ). Although a great strength of behavioral genomics is its ability to investigate genetic influence in samples of unrelated individuals, combining GWA genotypes with traditional quantitative genetic designs has also enriched causal modeling (McAdams et al. 2022 ), for example, by comparing results within and between families (Brumpton et al. 2020 ; Howe et al. 2022 ).

This whistle-stop tour has highlighted some of the milestones in a century of research in behavioral genetics. The progress is unmatched in the behavioral sciences and its discoveries have been transformative. The most exciting development is the synthesis of quantitative genetics and molecular genetics into behavioral genomics. The energy from this fusion will propel the field far into the future.

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Plomin, R. Celebrating a Century of Research in Behavioral Genetics. Behav Genet 53 , 75–84 (2023). https://doi.org/10.1007/s10519-023-10132-3

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Behavioral Genetics by Lisabeth DiLalla , Matthew Jamnik , Riley Marshall , Emily Pali LAST REVIEWED: 20 February 2024 LAST MODIFIED: 20 February 2024 DOI: 10.1093/obo/9780199828340-0010

Behavioral genetics is the study of genetic and environmental influences on behaviors. By examining genetic influence, more information can be gleaned about how both genes and the environment operate to affect behavior. Almost all behaviors studied by psychologists are affected by our genetic makeup, and so the question is not whether genes are important, but how do they affect these behaviors? The old nature–nurture debate has been laid to rest. We know, from thousands of studies using many different methodologies, that both genes and environment are important to understand if we hope to untangle the mysteries of virtually any behavior. Among the interesting questions to be asked now: How do genes and environments work together to influence behaviors? What specific genes might be responsible for various types of behaviors and what is their mechanism of action? The field of behavioral genetics is moving forward and changing so rapidly that many of the articles included here are from relatively recent work. Some essential mainstays are included that all students of behavioral genetics should read and that both help to explain the history of this field and also represent seminal papers that still hold true. However, a large number of the articles are representative of many comparable articles. This selection is intended to get the reader started on a foray into the area. It should be noted that most research articles in this field are quantitatively quite complicated. A reading knowledge of path analysis and structural equation modeling would be beneficial. However, even readers without this knowledge can glean sufficient information from these articles by skimming the results sections and concentrating instead on the literature reviews and discussion summaries.

There are several texts that provide an interesting overview of the field of behavioral genetics at large and some recent books that focus on topics relevant for specific subgroups. Kim 2009 is intended to be fairly general and cover a broad array of behaviors. Plomin 2018 , written for a lay audience, is accessible and presents important food for thought about the future of DNA in our everyday lives. DiLalla 2004 and McCartney and Weinberg 2009 are edited texts resulting from Festschrifts that present chapters broadly reviewing the behavioral genetics realm with a focus on work by Irving I. Gottesman (in DiLalla) and Sandra Wood Scarr (in McCartney and Weinberg), both of whom were seminal behaviors genetics researchers. Dick 2021 summarizes behavior genetics research as it relates specifically to parenting in a book written for a lay audience, and Harden 2021 provides a general discussion of how genetics research can benefit society in terms of justice and equality. Two books by Nancy Segal ( Segal 2005 and Segal 2017 ) provide information about twins specifically. Although not recent, these are included because they provide an excellent background into research on twins.

Dick, Danielle M. 2021. The child code . New York: Avery.

This book, written for parents, discusses parenting from the perspective of each child’s unique genetic make-up, or “code.” It clarifies the importance of each individual child’s contribution to the parent-child relationship and suggests ways to parent accordingly.

DiLalla, Lisabeth Fisher, ed. 2004. Behavior genetics principles: Perspectives in development, personality, and psychopathology . Washington, DC: American Psychological Association.

Resulted from a festschrift for Professor Irving I. Gottesman, a pioneer in behavioral genetics research. This book presents research spawned by Gottesman’s work and ideas, with a specific focus on development, personality, and psychopathology. Geared to researchers and students in the field.

Harden, Kathryn Paige. 2021. The genetic lottery: Why DNA matters for social equality . Princeton, NJ, and Oxford: Princeton Univ. Press.

DOI: 10.2307/j.ctv1htpf72

This book should be read with caution, but importantly attempts to clarify to introductory readers that genetic make-up accounts for socioeconomic inequality while simultaneously trying to discredit eugenics as a pseudoscience. Harden states that awareness of human genetic variability across individuals actually should lead to a more fair, equitable society.

Kim, Yong-Kyu. 2009. Handbook of behavior genetics . New York: Springer.

DOI: 10.1007/978-0-387-76727-7

Intended for students of genetics, psychology, and psychiatry. Chapters describe research in various areas of behavior including psychopathology, intelligence, and personality. Behavioral genetic relevance is discussed, as are cutting-edge methodologies and the directions these fields will take in the future.

McCartney, Kathleen, and Richard A. Weinberg. 2009. Experience and development: A Festschrift in honor of Sandra Wood Scarr . New York: Psychology Press.

Resulted from a Festschrift for Dr. Sandra Wood Scarr, an eminent developmental behavior geneticist. Chapters written by her students and colleagues cover topics based on Scarr’s research, such as heritability of cognitive ability in impoverished children, sibling relationships, and adoption. Intended for researchers of psychology, behavior genetics, and childcare.

Plomin, Robert. 2018. Blueprint: How DNA makes us who we are . Cambridge, MA: Massachusetts Institute of Technology Press.

Written for a lay audience, Plomin uses accessible terminology to explain complicated concepts and to tease apart the roles of genes and environment as they affect behaviors. Mostly based on evidence from his own research and large, genome-wide research projects. Bottom line: children’s development is primarily a function of their genetic make-up.

Segal, Nancy L. 2005. Indivisible by two: Lives of extraordinary twins . Cambridge, MA: Harvard Univ. Press.

An arresting book by Nancy Segal. She describes several sets of twins, triplets, and quadruplets to demonstrate how both genes and environment play critical roles in behavioral development.

Segal, Nancy L. 2017. Twin mythconceptions: False beliefs, fables, and facts about twins . London: Academic Press.

In this fun book, intended for professionals, parents, and others interested in twins, Segal identifies over seventy common misconceptions about twins and twinning. She explains each one using known scientific findings, with appendixes explaining some topics in more detail.

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The Genetics of Human Behavior

• Katherine Kim + −
• David Streid + −

Behavioral disorders arise from environmental, lifestyle, and genetic factors. Past studies have shown evidence for the hereditability of several major behavioral neuropsychiatric disorders, such as schizophrenia, depression, and bipolar disorder. In these cases, certain genetic defects are passed down from parental generations and increase an offspring’s risk of inheriting a specific disorder. While neuropsychiatric disease susceptibility cannot be attributed solely to genetics, it is important to study how one’s genetic makeup can affect various facets of human behavior. Uncovering this link between genes and behavior could lead to the discovery of new biological factors involved in the development of highly prevalent neurological responses and disorders.

A recent study in behavioral genetics has shown that there may be a genetic basis for irrational phobias. It highlights the possibility that phobias are a form of inherited defense mechanism passed down through familial genes. In this study, researchers Dias and Ressler from the Emory School of Medicine subjected mice to fear conditioning by exposing them to the scent of chemical acetophenone, which smells like cherry blossoms, before administering electric shocks to the mice. Offspring of these mice (which were not exposed to the same conditioning as their parents) showed fearful responses to the odor of acetophenone, even when smelling it for the first time. This demonstrated that they had acquired a phobia of the chemical odor.

Structural abnormalities were also discovered in the olfactory bulbs of the offspring mice. Upon sequencing the mice’s sperm DNA, Dias found that the gene encoding M71, an odo receptor activated by acetophenone, was methylated in the conditioned parental and direct offspring generations. However, it is unknown whether this epigenetic alteration in sperm DNA was responsible for the offspring’s heightened odor sensitivity. It is possible that different biological mechanisms worked in conjunction to translate the inherited ancestral experiences to irrational phobias in the offspring.

Other studies in behavioral genetics have shown that some neuropsychiatric disorders are less heritable—or have a weaker genetic component—than others. For example, while genes may account for more than half of the risk for certain neuropsychiatric disorders, such as schizophrenia or bipolar disorder, the hereditability of anxiety and depression appear to be lower. According to Dr. Pine at the Cold Spring Harbor Laboratory, approximately 30-50% of the risk for anxiety and depression is genetic, while the other 50% to 70% of the risk may be attributed to environmental factors, such as substance use, stress, diet, and childhood experiences.

Anxiety disorders are the most common form of mental illness in the U.S., affecting 18% of the total population. Depression is also common, with around 10% of Americans experiencing a major depressive disorder at some point in their lives. Despite the high prevalence, genetic disposition for anxiety and depression is weak when compared to other neuropsychiatric disorders. As scientists, we must determine why this is the case. Is it due to a difference in the number of gene defects? For example, are there less genetic variations linked to anxiety and depression than to other more heritable diseases? Or are depression/anxiety genes less evolutionally conserved? Only by answering these questions can we get a firm understanding of the genetic root of these conditions and develop ways to prevent or fight the disorders.

We must examine the gene defects themselves. Perhaps, in behavioral disorders with relatively low heritability, the gene variations only minimally disrupt the major pathways of the brain. In such cases, it would be wise to study non-genetic factors that trigger the behavioral response. In addition, a psychodynamic treatment approach – alleviating a patient’s mental tension with the help of a psychiatrist—may be more helpful than invasive medical procedures. On the other hand, personalized medicine, such as gene therapy, may be the best option for treating significantly inheritable disorders, like schizophrenia. Through advancements in gene testing, doctors are able to conduct pre-symptomatic diagnostic tests to see the risk for patients with a family history of inherited neurological disorders. Tests can detect abnormalities, which may include missing or heavily altered sections of a gene, or genes that are inactive or lost, in DNA or RNA samples of patients. In other cases, a test may detect excessive RNA from a single gene, indicating that it is overexpressed in the body. Identifying and fixing these problematic sequences in the genetic code requires extensive knowledge of the human genome. Physicians providing personalized medicine must take into account a patient’s genetic makeup to determine the best form of targeted treatment for an illness.

Through genetic research, we are slowly beginning to unravel the biological basis for many neuropsychiatric disorders. Understanding the role of genes in highly prevalent neurological responses, like anxiety and phobias, is crucial for designing effective treatments tailored to patients who are suffering these conditions. Specifically, by identifying the genetic markers associated with inheritable neuropsychiatric diseases, we can analyze a patient’s risk of disease inheritance and responsiveness to existing medical treatment. This knowledge will make a powerful impact on the medical community and the future of medicine.

This work is licensed under a Creative Commons Attribution 4.0 International License .

Genetics and Addiction: What We've Learned

New research offers insights on numerous addiction-related genes..

Updated April 18, 2024 | Reviewed by Gary Drevitch

• Genetic and environmental risks affect the incidence and course of substance use disorders.
• Progress in genetics research provides information on numerous addiction-related genes.
• Genetics helps doctors provide individualized advice and patients to make personalized medicine choices.

Are you mostly a product of the genes you inherit or your experiences in life? This question intrigues many people, including addiction researchers. In this post, I provide an overview of key research on the genetic inheritance of substance use disorders such as alcohol use disorder, opioid use disorder, and cannabis/marijuana use disorder.

Some researchers, such as at the Washington University School of Medicine in St. Louis, seek to identify genes common to addictive disorders based on information from the DNA code of more than a million people. So far, these researchers have identified 47 genetic variants linked to substance disorders, including 32 for tobacco, 9 for alcohol, 5 for cannabis, and one for opioid addiction.

Alcohol Use Disorder

Alcohol use disorder (AUD) has been studied for years, starting with twin studies comparing identical or fraternal twins and their risk for AUD and adoption studies comparing adopted children to their birth parents. These studies demonstrated that the heritability of alcohol dependence is up to 60%. Some genes increase a person’s risk for AUD, while others decrease that risk directly or indirectly. For instance, some people of Asian descent carry a gene variant altering their rate of alcohol metabolism, causing symptoms like flushing, nausea, and rapid heartbeat when they drink even a little alcohol. These genes may help protect them from developing AUD.

Twenty-two percent of adults in the United States have at least one biological parent with alcohol use disorder (AUD). The odds of lifetime AUD are 2.5 times higher for the offspring of one AUD parent and 4.4 times higher for the offspring of two AUD parents, as compared to children of non-AUD parents.

AUD Protections and Risks

Genes are not destiny, and environmental experiences also play a role. For example, a study of more than 3 million people suggests that marriage may protect against AUD, particularly for those with genetic loading for AUD. However, researchers also noted that while marriage to a spouse without alcohol problems may protect against alcohol use disorders, being married to a spouse with alcohol use problems has the opposite effect, increasing one's risk.

It is also known that pain , either psychological or physical, as well as PTSD and trauma , can make AUD more likely, as the additive relief of distress seems to increase brain-related rewards derived from alcohol.

Currently, treatment of AUD is limited to only several FDA-approved and a few non-approved drugs which often have only modest effects in inhibiting drinking, largely because they work well only for certain individuals. But thanks to new research, we now know which individuals are most likely to respond significantly better to one often-used AUD treatment: naltrexone.

Raymond Anton, Jr., MD is an international expert on alcohol use disorder, an addiction psychiatrist, and clinical neuroscientist , as well as researcher of genetic variants predicting treatment-response to AUD medications such as naltrexone. He and his colleagues discovered that it was not one gene, but rather a combination of genes known to affect key brain chemicals impacted by alcohol that made a difference in whether naltrexone was effective in people with AUD. For example, in two different studies, they found that a gene variation known to impact the brain opiate receptor gene, combined with variations in two genes thought to control brain dopamine , influenced how well naltrexone worked in reducing/controlling drinking in individuals with AUD. The first study evaluated genes inherited from one’s parents (germ line mutations) and the second evaluated epigenetic markers (likely acquired over a lifetime). Epigenetic markers refer to changes to gene functioning occurring in life secondary to behavior (such as drinking alcohol) or various outside influences such as other diseases, stress , etc.

As a result of Anton’s research, it’s clear that personalized treatment and choosing the right medication for the right patient is becoming possible in AUD. For example, performing a few relatively simple genetic tests identifying variations in three brain genes will enable physicians to predict which patients would benefit most from taking naltrexone, an FDA-approved medication for AUD. If tests show patients will not benefit, other medications could be tried. Alternatively, new medications might be developed based on genetic testing results. Rather than taking a drug that could never work well because of one’s genetic makeup, wouldn’t it be best to know this upfront and potentially choose an alternative? Also, knowing a drug is likely to work might encourage more people to consider medication-assisted treatment.

Developmental Pathways

Early life experiences, such as childhood trauma, parental alcohol use, and exposure to alcohol during critical periods of brain development, may have lasting effects on neurobiological systems involved in addiction. These environmental influences may interact with genetic predispositions, shaping an individual's vulnerability to AUD. Early alcohol or drug experimentation; physical, sexual , or emotional trauma; and other risk factors, such as second- or third-hand smoke exposure, abusive parenting , parental substance use, and other factors also play a role.

Opioid Use Disorder

Sometimes, the environment plays a key role in the development of a disorder. The findings in one study showed that environmental factors explained more of the risk for opioid dependence than polygenic risk scores—a number estimating how genetic variants affect an individual's risk of developing a disease. Polygenic risk scores combine different versions of many genes related to a specific disease. The researchers found selected environmental factors, such as annual household income and education level, explained an average three-fold greater risk for opioid use disorder (OUD) compared with opioid use disorder polygenic risk scores alone.

But don’t count out genetics. Although researchers found environmental factors played a larger role, opioid polygenic risk scores explained 8% of the variance of the risk for opioid dependence. The study also found that among people with higher polygenic risk scores, individuals with a higher education level were less likely to have opioid dependence, whereas those with posttraumatic stress disorder (PTSD) were more likely to have opioid dependence.

A new study by Yale School of Medicine researchers assessed how genetic and psychosocial predictors of opioid use disorder are predictive for a person becoming dependent on opioids. In the VA and Yale study, researchers analyzed genetic data from nearly 2,000 people who participated in a prior study by Yale and University of Pennsylvania researchers (called the Yale-Penn study) on substance use genetics. Researchers examined the role of recently developed polygenic risk scores for opioid use disorder and environmental factors such as education level, adverse childhood experiences , and psychiatric conditions. “We’ve made great progress in understanding some of the genetic and environmental factors that influence risk for opioid use disorder, but we know less about the complex interplay between them,” said Yale’s Joseph Deak.

Cannabis Use Disorder

Marijuana is the most commonly used federally illegal drug in the United States, with half of all Americans saying they have tried it at some time. Experts estimate that among people who use cannabis , up to 30% may have marijuana use disorder (which is the same as cannabis use disorder, or CUD). The risk of developing cannabis use disorder is greater in people who start using marijuana during youth or adolescence and who use marijuana more frequently.

It has been estimated that 50%-70% of an individual’s risk for cannabis use disorder is due to genetic factors , although environmental factors also play a role. Yale’s group, led by Joel Gelertner , has been trying to identify these risks and predict who might develop cannabis use disorder, with its many negative outcomes, including increased risk of psychiatric disorders, heart disease, cancer, and respiratory illnesses.

Researchers examined a genome-wide set of genetic variants in individuals from multiple ancestry groups enrolled in the U.S. Department of Veterans Affairs’ Million Veteran Program, one of the world’s largest genetic databases. They identified dozens of genetic variants linked to cannabis use disorder and a variety of behavioral and health issues associated with CUD.

The findings offer insights into genetic factors and potentially related health risks. For instance, researchers found that variants of genes encoding for three different types of receptors on neurons were associated with an elevated risk for developing CUD. In addition, variants linked to CUD were associated with the development of lung cancer. The authors noted that more work needs to be done to separate the effects of tobacco use and other environmental factors on cancer diagnoses from those of marijuana use.

Genetics researchers have leveraged new CUD genomics data to complete a genetically-informed analysis with unprecedented power, which showed causal relationships between CUD and with risk for developing SUDs in April 2024. This new finding is the strongest evidence to date that cannabis use disorder and even cannabis use significantly increases the risk for other substance use disorders.

Personalized Medicine

Personalized medicine in addiction treatment could revolutionize the current approach to substance use disorders. Here's how:

Genetic and pharmacogenomics testing. As with cancer treatment, genetic testing could identify individuals predisposed to addiction or who may respond differently to certain medications used in addiction treatment. For example, certain genetic variations might influence how a person metabolizes and responds to medications like naltrexone, methadone, or buprenorphine, all used in opioid addiction treatment. Biomarkers also could help predict individuals who may be at higher risk of relapse .

Behavioral lifestyle and psychological profiling. Personalized medicine in addiction treatment considers individual differences in behavioral and psychological factors. Tailored interventions could include advice on exercise, diet , and sleep, and providing relapse-prevention counseling, support groups, vocational training, housing assistance, and other resources based on a patient’s specific needs and circumstances.

Anton RF,et al . Opioid and Dopamine Genes Interact to Predict Naltrexone Response in a Randomized Alcohol Use Disorder Clinical Trial. Alcohol Clin Exp Res. 2020 Oct;44(10):2084-2096. doi: 10.1111/acer.14431. Epub 2020 Sep 19. PMID: 32772383; PMCID.

Polimanti R, et al. Multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidality. Transl Psychiatry. 2021 Jan 11;11(1):34. doi: 10.1038/s41398-020-01153-1. PMID: 33431810; PMCID: PMC7801457.

Galimberti, M., et al. Genetic influences and causal pathways shared between cannabis use disorder and other substance use traits. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02548-y

Zhou, H., et al. Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals. Nat Med 29, 3184–3192 (2023). https://doi.org/10.1038/s41591-023-02653-5

Mark S. Gold, M.D., is a pioneering researcher, professor, and chairman of psychiatry at Yale, the University of Florida, and Washington University in St Louis. His theories have changed the field, stimulated additional research, and led to new understanding and treatments for opioid use disorders, cocaine use disorders, overeating, smoking, and depression.

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• Published: 29 April 2024

Inclusion of the severe and enduring anorexia nervosa phenotype in genetics research: a scoping review

• Sarah Ramsay 1 ,
• Kendra Allison 2 ,
• Heide S. Temples 2 ,
• Luigi Boccuto 1 &
• Sara M. Sarasua 1  

Journal of Eating Disorders volume  12 , Article number:  53 ( 2024 ) Cite this article

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Anorexia nervosa has one of the highest mortality rates of all mental illnesses. For those who survive, less than 70% fully recover, with many going on to develop a more severe and enduring phenotype. Research now suggests that genetics plays a role in the development and persistence of anorexia nervosa. Inclusion of participants with more severe and enduring illness in genetics studies of anorexia nervosa is critical.

The primary goal of this review was to assess the inclusion of participants meeting the criteria for the severe enduring anorexia nervosa phenotype in genetics research by (1) identifying the most widely used defining criteria for severe enduring anorexia nervosa and (2) performing a review of the genetics literature to assess the inclusion of participants meeting the identified criteria.

Searches of the genetics literature from 2012 to 2023 were performed in the PubMed, PsycINFO, and Web of Science databases. Publications were selected per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). The criteria used to define the severe and enduring anorexia nervosa phenotype were derived by how often they were used in the literature since 2017. The publications identified through the literature search were then assessed for inclusion of participants meeting these criteria.

most prevalent criteria used to define severe enduring anorexia nervosa in the literature were an illness duration of ≥ 7 years, lack of positive response to at least two previous evidence-based treatments, a body mass index meeting the Diagnostic and Statistical Manual of Mental Disorders-5 for extreme anorexia nervosa, and an assessment of psychological and/or behavioral severity indicating a significant impact on quality of life. There was a lack of consistent identification and inclusion of those meeting the criteria for severe enduring anorexia nervosa in the genetics literature.

This lack of consistent identification and inclusion of patients with severe enduring anorexia nervosa in genetics research has the potential to hamper the isolation of risk loci and the development of new, more effective treatment options for patients with anorexia nervosa.

Plain English Summary

Anorexia nervosa (AN) is a serious illness with a high death rate. Many of those with AN do not recover and have continuing severe psychological and physical symptoms that greatly impact their quality of life. Research has shown that genetics plays an important role, along with environment, in the development and persistence of AN. This review highlights the continued lack of consensus on defining criteria for severe and enduring AN in the literature and the continued focus on younger females with shorter illness durations in AN genetics research. Greater efforts are needed to include older participants with severe AN of longer duration in genetics research in hopes of developing more effective treatments for this underrepresented group.

Anorexia nervosa (AN) is a devastating illness with a high mortality rate. The standardized mortality ratio (SMR) calculates whether those in a given study population are equally, more or less likely to die compared to a reference population [ 1 ]. With an estimated SMR between 5.9 and 15.9 (i.e., 6–16 times excess mortality), AN is considered one of the deadliest mental disorders [ 2 , 3 ].

Studies indicate that the overall incidence rate for AN has remained relatively stable (4% female lifetime-0.3% male lifetime) since the 1970s [ 2 , 4 ]. The symptomology and presentation of AN have evolved along cultural lines; however, it is not simply a manifestation of modern cultural and social pressures. Accounts of deliberate self-starvation date back to the beginning of written history [ 5 ].

Although the exact etiology of AN is still unclear, a substantial body of evidence indicates that genetics plays a considerable role [ 6 , 7 ]. Genetic studies dating from the late 20th century have shown that AN is highly familial. The lifetime risk of developing AN for female relatives of individuals with AN is 11 times greater than that for female relatives of individuals without AN [ 8 ]. Heritability (h 2 twin ) estimates from twin studies range from ∼ 48–74% [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. The large range in estimates may be due to the use of broader participant inclusion criteria in AN studies to increase study group size. Broadening the inclusion criteria results in a more heterogeneous sample and decreased heritability estimates, while narrowing the definition of AN yields higher and more consistent estimates [ 17 ].

Although recovery from AN is possible, for approximately 20% of affected individuals the condition takes on a more intractable phenotype [ 18 , 19 ]. While AN symptoms vary from person to person, it has been suggested that a unique severe and enduring anorexia nervosa (SE-AN) subtype exists; however, aligning on clear defining criteria has proved challenging [ 20 ].

Since the 1980s, a small number of literature reviews of varying breadth and depth have been conducted in attempts to better define SE-AN. The most comprehensive to date, a 2017 review by Broomfield and colleagues identified illness duration and previous unsuccessful treatment as the criteria most often used in the literature to define AN severity [ 21 ]. A 2018 editorial by Hay and Touz, which referenced the Broomfield review, expanded the suggested criterion to include significantly diminished quality of life and narrowed the duration criterion to a minimum of three years and the therapeutic intervention exposure criterion to at least two previous evidence-based treatments [ 22 ]. In a 2021 follow-up review, with the aim of defining a neuropsychological profile for SE-AN, Bloomfield et al. identified intelligence, set-shifting and decision-making as features warranting further attention and noted that additional data are needed to align on defining severity criteria [ 23 ]. In short, there continues to be a lack of consensus on how to best define SE-AN.

Psychiatric illness is often diagnosed in a binary manner; an individual is assessed as either having the illness or not. In reality, due to their complex nature, psychiatric illnesses are better defined on a continuum [ 24 , 25 ]. Genome-wide association studies (GWAS) often use a binary case-control design. However, as Yang et al. [ 26 ] noted, with an equal population sample size, a quantitative trait (for example, symptom severity) association study will have greater power than a case-control association study. The difference is because in a case-control study, an individual with mild symptoms is not differentiated from one with severe symptoms. Relating this to AN, there would be no differentiation between an individual who met the DSM-5 criteria for mild illness, of short duration and who was responsive to first-line treatment, and an individual who met the extreme illness criteria, with a duration of over a decade and lack of positive response to multiple treatment modalities. Delineating participants based on illness severity when performing genetic data analysis of those with AN may improve the chances of identifying significant variants.

The potential value of defining more phenotypically similar groups based on quantitative phenotypes and comorbidities in genetic studies of psychiatric illness has been demonstrated in major depressive disorder (MDD), schizophrenia, autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) [ 27 , 28 , 29 , 30 ]. Individuals with more severe MDD symptoms have been found to have increased genetic risk for other psychiatric disorders [ 29 ], and polygenic risk scores (PRS) for schizophrenia correlate with symptom severity [ 28 ]. Genetic risk score (GRS), PRS and polygenic score (PGS) are the terms most often used in the literature when referring to values estimating an individual’s lifetime risk of developing a phenotype (disorder) based only on their genetics [ 31 ]. The scores are generated by combining the number of risk alleles at all the risk variants in an individual’s genome. Disease-associated risk variants are based on the latest and most comprehensive GWAS for the disorder at the time of the analysis.

Studies delineating and comparing subgroups of individuals with AN based on defined quantitative criteria may result in the discovery of rare variants associated with symptom severity, and individuals manifesting a more severe phenotype may be more likely to show higher heritability estimates and thus represent a subgroup of patients for which genetics findings may be beneficial. However, this hypothesis cannot be adequately tested to the rigorous standards required without a more precise definition of what constitutes a severe and enduring phenotype, and greater attention given to specifically identifying and including this group in genetic studies [ 32 ].

The aim of this review is to first, as an extension of the Broomfield et al. review [ 21 ], identify the criteria most widely used to describe the phenotypic severity of AN by including articles published since 2017 and, second, evaluate the genetics literature for inclusion of individuals meeting these criteria.

Delineating criteria for the severe and enduring anorexia nervosa phenotype

To better identify and delineate research participants manifesting a severe and enduring phenotype in the genetics literature, it was necessary to discern the most often used defining criteria for this subgroup of AN. The terms Anorexia Nervosa AND severe AND (Enduring OR Chronic) were used, with no year limit, to search titles and abstracts in PubMed, PsycINFO, and Web of Science. Articles were also limited to human subjects.

One of the articles identified was an extensive review by Broomfield et al. of how the literature labeled and defined AN severity up to 2017 [ 21 ]. The current search was limited to articles published after the Broomfield 2017 review to focus on the most recent literature. The references were not required to be attempting to empirically define a severe or enduring anorexia nervosa phenotype. The goal was to determine how those with a longer lasting and more severe clinical presentation are currently referred to in the literature. After removing commentaries on other references, clarifications, and updates from previous studies with the same authors and criteria, redundant references, and those not referring to a severe or enduring anorexia nervosa phenotype, 37 publications remained. Of these 37 publications, there were 22 research papers (6 clinical trials, 16 studies), 4 case reports, 6 expert panel/position papers/or opinion/editorial papers, 2 literature reviews and 3 general reviews. These references are listed in Table  1 , along with a book chapter [ 33 ] identified through reviewing the references of the selected papers, that was not included in the Broomfield 2017 review, bringing the total publications included to 38. The mean age, mean BMI, duration of illness in years, and history of previous treatment, as well as any other measures of illness severity, were extracted from the articles and are shown in Table  1 . A second reviewer, using the RANBETWEEN function in Microsoft Excel, selected 10% of the articles at random from Table  1 . to review for meeting inclusion criteria and accuracy of the data extracted.

Articles were reviewed to determine which criteria are used most often in the literature in regard to the severe enduring phenotype. Specifically, articles with a central purpose of better defining a severe and or enduring/chronic AN phenotype or the need for better treatment options (for example [ 34 , 35 ]), and articles including case studies or participants in one or more study groups defined as having a severe and or enduring/chronic AN phenotype (for example [ 36 , 37 ]) were included. The tabulation from the Broomfield review was combined with the current total. Given that the four Dalton articles referenced the same data, they were counted as only one reference. The results are outlined in Fig.  1 .

Number of references from Table  1 representing the specific duration of illness, number of previous unsuccessful treatments and body mass index (BMI) subgroups indicated either in defining severe and enduring anorexia nervosa or as inclusion criteria for participants. The totals indicated include both the references from the 2017 Broomfield review [ 21 ] and the current work

Literature review: inclusion of participants meeting the severe and enduring AN phenotype in genetics research

The search outlined in this section followed the process depicted in the PRISMA flow diagram [ 38 ] in Fig.  2 , which captures the literature selection flow. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist was utilized [ 39 ]. The goal was to assess whether participants meeting the criteria identified as the most widely used to define a severe and enduring phenotype are being included in genetics research, and, if included, whether these participants were assessed as an independent group.

PRISMA flow diagram for the literature search

The terms Anorexia Nervosa AND (genetic OR gene OR hereditary) in titles and abstracts were used for the following searches. Articles were limited to human subjects, and review articles were excluded. The goal was to be as inclusive as possible in the initial searches of each database. The search was limited to the last decade of published literature to assess current practices in genetics research. This span of time encompasses the five years leading up to and following the identification of the first genome wide significant locus for AN [ 40 ] and the publication of Broomfield et al., both of which were published in 2017. The inclusion dates were as follows: PubMed, 1-Jan-2012 to 6-Oct-2023 (date of search); PsycINFO, 1-Jan-2012 to 10-Oct-2023 (date of search); and Web of Science, 1-Jan-2012 to 12-Oct-2023 (date of search).

Searches of PubMed, PsycINFO and Web of Science conducted with the search criteria resulted in 240, 206 and 235 hits, respectively. Titles and keywords were reviewed, and 277 articles were eliminated for redundancy (see “identification” in Fig.  2 ). During the first screening, the abstracts for the remaining 404 were reviewed, and 211 were eliminated for the reasons depicted in the PRISMA diagram (“Records selected for Review 1”). The remaining 193 publications progressed to the second screening.

In the second screening, noted as “Records selected for Review 2” in the PRISMA diagram, the methods sections of the remaining 193 articles were reviewed for details on age, psychological assessments, anorexia subtype, duration of illness, prior treatment history, and other indications of disease severity. Studies did not need to specifically call out a subgroup of participants as being severe and or enduring; however, those not including participant data for at least three of the following four criteria were eliminated because they did not provide adequate information for the assessment of participant phenotype severity and intractability: (1) duration of illness; (2) body mass index (BMI); (3) prior treatment history; and (4) severity as measured by one or more clinical, social, or psychological scales. This resulted in the elimination of an additional 115 articles. A total of 78 articles were ultimately included in the information extraction process; the results are presented in Table  2 .

The data were extracted by reviewing both the methods and results sections of each paper for the following participant data: (1) mean duration of illness in years; (2) mean BMI in kg/m 2 ; (3) prior treatment history; (4) and severity as measured by one or more clinical, social, or psychological scales. Participant gender, mean age, and groups of eating disorders included in the studies (i.e., AN-restricting, AN-binge purge, bulimia, binge eating) were also extracted. A second reviewer, using the RANBETWEEN function in Microsoft Excel, selected 10% of the articles at random from Table  2 to review for meeting inclusion criteria and accuracy of the data extracted.

Defining severe enduring anorexia nervosa in the research literature

A review of the literature revealed that the terms severe, chronic, and enduring identified by Broomfield et al., in 2017 [ 21 ] continue to be widely used to label the more intractable AN phenotype. How these labels are defined in the literature, when they are defined, continues to vary greatly. The age of study participants, BMI, duration of illness, and previous treatment history were extracted from each reference and are recorded in Table  1 .

The primary inclusion criteria presented in the articles reviewed were as follows:

The Broomfield review [ 21 ] identified duration as the primary criterion used to define the severe and enduring AN phenotype, and this continues to be true. Several articles reviewed included duration of illness as a criterion for inclusion in their study or clearly delineated a subgroup using duration as one criterion. The stringency of how duration was measured varied.

In their audit of care received by patients with “early stage” versus “severe and enduring” AN, Ambwani et al. [ 36 ] defined a duration of < 3 years for early stage and ≥7 years for severe and enduring AN, as recommended by Robinson et al. and Touyz et al. [ 41 , 42 ]. This was also the case for Calugi et al. [ 43 ], who used ≥7 years in their study of cognitive behavioral therapy effectiveness. The patient described in the case study by Voderholzer et al. [ 44 ] had AN for seven years. In the four papers by Dalton et al. studying the impact of transcranial magnetic stimulation on severe and enduring AN, the duration inclusion criterion for study participation was ≥3 years of AN symptoms [ 45 , 46 , 47 , 48 ]. Whereas Knyahnytska et al. [ 49 ] included a duration of > 5 years as a criterion for treatment resistance in their insula H-coil transcranial stimulation therapy study. In the selection of a subset of participants from the Anorexia Nervosa Genetics Initiative (ANGI) to include in their assessment of the polygenic association of severity and long-term outcome in AN, Johansson et al. [ 50 ] included in their criteria for the severe enduring subtype a ≥ 5 year follow-up time, defined by the authors as years between initial registration and ANGI recruitment. Finally, in two of the three studies evaluating the effectiveness of deep brain stimulation, an illness duration of ≥ 10 years was required for participant inclusion [ 51 , 52 ], with the third requiring > 7 years [ 53 ]. Case study, clinical trial and study participants included in groups indicated as manifesting a severe and enduring phenotype tended to have illness of longer duration. For example, participants in the Calugi et al. [ 43 ] study had a mean duration of 12.3(4.7 SD) years, and the three case study subjects had illness durations of 7 [ 44 ], 11 [ 54 ], 25 [ 55 ], and 26 [ 37 ] years.

Position papers, commentaries, and reviews also varied greatly in defining duration requirements. For example, in their German language case study on palliative care for severe AN, Westermair et al. [ 56 ] proposed a long duration of illness, e.g., 10 years, as a criterion, whereas Hay and Touyz [ 22 ] and Herpetz-Dahlmann [ 57 ] used a duration of > 3 years. Other authors fell between the two extremes; Bianchi et al. [ 58 ] defined severe and enduring AN participants as those who had the disorder for six years or more, and Marzola et al. [ 59 ] used a seven-year demarcation. However, these two papers also proposed that duration should not be used alone when defining AN severity. The usefulness of duration as a criterion was also questioned by Wildes et al. [ 60 ]. In an attempt to define the severe and enduring phenotype empirically, Wildes found no evidence for a chronic subgroup of AN, instead proposing that this group may be better classified on the basis of impact on quality of life and severity of injurious behaviors. As indicated in Fig.  1 , a duration of 7 or more years was used most frequently, followed by 10 years.

Body mass index (BMI):

The DSM-5 defines four levels of AN severity: mild, BMI greater than 17 kg/m 2 ; moderate, BMI of 16–16.99 kg/m 2 ; severe, BMI of 15–15.99 kg/m 2 ; and extreme, BMI of less than 15 kg/m 2 [ 61 ]. Once again, the literature indicates a wide range of BMIs in articles attempting to define severe and enduring AN and/or for participation in studies targeting this group of individuals. The two studies of deep brain stimulation with duration criteria of ≥ 10 years for participation also had BMI requirements falling into the DSM extreme category [ 51 , 52 ]. Deep brain stimulation involves a high degree of risk, and the authors delineated that only individuals with the most severe cases should be included. Similar to duration of illness, participants included in groups indicated as manifesting a severe and enduring phenotype in case studies, clinical trials and studies, tended to have substantially lower BMIs than required per the inclusion criteria. For example, participants in the Bemer et al. bone mineral density (BMD) study had a mean BMI of 12.60 ± 1.60 kg/m 2 , which was well below the < 16 kg/m 2 criteria [ 62 ].

Notably, several studies included a low weight cutoff for participation. For example, in their transcranial magnetic stimulation studies, Dalton et al. [ 45 , 46 , 47 , 48 ] required a BMI > 14 kg/m 2 for participation. The reason provided in the study protocol for the low weight cutoff was “safety precaution” [ 63 ]. The deep brain stimulation studies conducted by Park et al. [ 64 ] required that participants be severely underweight but with a low-weight BMI criterion of > 13 kg/m 2 . Although reasons were not given for the low weight cutoff, they stated that participants needed to have a BMI > 13 kg/m 2 for surgery, which is understandable given its invasive nature.

Again, as with duration of illness, the literature suggests that BMI should not be used as the sole determinant of severity in AN. In their editorial on the challenges of defining severe and enduring AN, Hay and Touyz [ 22 ] recognized the utility of the DSM-5 BMI severity categories but also noted that for those with unremitting AN for a decade or more, having a BMI above the DSM severe range is still associated with marked morbidity.

Psychological assessment:

All the studies reviewed included an assessment of symptoms such as psychological stress, disordered eating, depression, anxiety, obsessiveness, and quality of life. For example, Wildes et al. [ 60 ], used the Research and Development Corporation (RAND) 36-Item Health Survey 1.0 (SF-36) to measure health-related quality of life, and found that these scores better classified AN subgroups than BMI and duration of illness. A score of ≤45 on the Global Assessment of Functioning (GAF) found in the DSM-4, which assesses the severity of mental illness [ 65 ], was used by Oudijn et al. [ 51 ] for inclusion in their deep brain stimulation studies. A plethora of tools was used in assessing eating disorder pathology, with the Eating Disorder Examination Questionnaire (EDE-Q) [ 66 ] and/or various iterations of the EDE-Q being the most prevalent.

Treatment response:

Lack of positive response to prior treatment, variously described as treatment resistance, treatment refractoriness, and failure to respond, was also included in assessing AN severity in several of the articles. The number and type of previous treatments required for inclusion in studies varied. For inclusion in deep brain stimulation studies, Park et al. [ 67 ] required a lack of positive response to ≥2 “typical modes” of treatment, as did Oudijn et al. [ 51 ]. The participant inclusion criteria used by Dalton et al. [ 48 ] for transcranial stimulation studies included the need to have completed at least one “previous course of National Institute for Health and Care Excellence” recommended “specialist psychotherapy or specialist day-patient or inpatient treatment”. The clearest classification criterion for treatment resistance was proposed by Hay and Touyz et al. [ 68 ]: “exposure to at least two evidence-based treatments delivered by an appropriate clinician or treatment facility together with a diagnostic assessment and formulation that incorporates an assessment of the person’s eating disorder health literacy with an assessment of the person’s stage of change”, which was referenced in the reviews of treatment options for those with severe enduring AN by Zhu et al. and Wonderlich et al. [ 20 , 69 ]. In contrast, Smith and Woodside [ 70 ] defined treatment resistance as “patients with two or more incomplete inpatient admissions and no complete admissions”. Emphasis was placed on patients failing to complete treatment rather than the treatment failing to help patients, although the authors did note that approximately 10% of patients treated at their inpatient facility were “unable to benefit”. As indicated in Fig.  1 , the criterion of two or more treatment attempts was most frequently used.

In summary, the literature indicates that a combination of assessments and criteria, including an illness duration of ≥ 7 years, lack of positive response to at least two previous evidence-based treatments, a BMI meeting the DSM-5 for extreme AN, and an assessment of psychological and/or behavioral severity indicating a significant impact on quality of life, were the most prevalent means of defining the severe and enduring AN phenotype. As the DSM-5 includes clear definitions of severe and extreme BMI (15–15.99 kg/m 2 and < 15 kg/m 2 , respectively), the criteria for severe BMI were also used in assessing the genetics literature in the following section.

Inclusion of participants meeting severe enduring anorexia nervosa-defining criteria in studies of anorexia nervosa genetics

The 78 articles identified as meeting the search criteria defined in the methods section were assessed for whether the following inclusion criteria were used and how they were defined:

Duration of illness,

Prior treatment history,

Severity as measured by one or more clinical, social, or psychological scales.

As mentioned previously, neither the statistical strength of the studies nor the study outcomes were assessed, as the purpose was to determine whether genetic studies included those meeting the severe and enduring phenotype criteria defined in the first aim through assessing prevalence of use in the literature. The studies consisted of Genome-Wide Association Studies (GWAS) as well as analyses of polymorphisms, expression, and gene methylation, including but not limited to the leptin ( LEP ) and the leptin receptor ( LEPR ) genes, the fat mass and obesity-associated gene ( FTO ), and the oxytocin receptor ( OXTR ) gene [ 16 , 71 , 72 , 73 ]. The gender of the study participants was also recorded where reported (Table  2 ).

Most of the 78 articles, including those specifically stating that the study was of severe AN, did not include criteria defined in the first aim. Most notably, only one article specifically stated that participants included had at least one prior treatment attempt [ 50 ].

Of the 71 studies reporting mean BMI, the mean BMI for all groups was 15.73 kg/m 2 (SD 1.48). For 15 studies (21%), the mean BMI was > 17 kg/m 2 (mild DSM-5). Sixteen studies (22%) had a mean BMI of 16–16.99 kg/m 2 (moderate DSM-5). Twenty-three studies (32%) had a mean BMI of ≤15.99 kg/m 2 (severe DSM-5), and 17 studies (21.8%) included at least one group with a mean BMI of ≤15 kg/m 2 , required to meet the DSM-5 definition of extreme AN. Only one study included a lifetime minimum BMI of ≤15 kg/m 2 as an inclusion criterion [ 74 ].

The duration of illness and or minimum duration required for inclusion in studies were reported for 23 (29%) of the 78 articles. Of those 23 studies, 3 (13%) had participants with a mean duration of illness ≤ 3 years, 12 (52%) had a mean of 3.1–6.99 years, and 6 (26%) had a mean of ≥ 7 years. Five of the 23 studies required a duration of illness ≥3 years as a participant inclusion criterion. None of the articles identified required duration of illness ≥7 years as an inclusion criterion.

Assessment of psychological stress, disordered eating, depression, anxiety, obsessiveness, and quality of life was another facet of defining the severity of AN in the studies evaluated. Across the 54 studies identifying defined assessment modalities, 38 different tools, checklists and guidelines were used in various combinations, including the following: Hamilton Anxiety Rating Scale (HARS), Clinical Global Impression anxiety scale (CGI), State-Trait Anxiety Inventory form (STAI); depression: Beck Depression Inventory (BDI), Children’s Depression Inventory (CDI), Montgomery-Asberg Depression Rating Scale (MADRS); alexithymia: Toronto Alexithymia Score (TAS); obsessive-compulsive and impulsive symptoms: Young-Brown Obsessive-Compulsive Symptoms (YBC-EDS), Leyton Obsessional Inventory-Child Version (LOI-CV); Barratt Impulsiveness Scale (BIS); and perfectionism: Child and Adolescent Perfectionism Scale (CAPS). Numerous eating disorder assessment tools, including the Eating Disorders Inventory (EDI), Eating Disorder Examination Questionnaire (EDE-Q), Eating Attitudes Test (EAT), and the Structured Interview for Anorexia and Bulimia Nervosa (SIAB) were also used. Table  3 shows a list of tools and how often they were used.

Historically, the focus of AN research has been on teens and young adults. The current assessment found that, of the 71 studies in which the mean age was reported or could be calculated, the mean of the mean ages reported for study participants was 20.9 (4.26 SD) years. Furthermore, the reported mean age of study participants in 36 (51%) of the 71 studies was ≤19.9 years, 21 (30%) had a mean age of 20-24.9 years, 14 (20%) had a mean age of 25-29.9 years, and only one study had an overall group mean age of ≥ 30 years, although eight studies included individual groups with means ≥ 30 years. Figure  3 provides a summary of the BMI, age and duration findings discussed above.

Number of articles in Table  1 representing the body mass index (BMI), age and duration subgroups indicated. NR = Not reported. A. BMI: 71 of the 78 articles reported BMI (kg/m 2 ), 17 of those 71 had participant mean BMI ≤ 15; Age: 72 of the 78 articles reported age, of those 72, one had a mean participant age over 30 years; Duration: 23 of the 78 articles included duration, of those 23, 6 had participant mean illness duration of ≥ 7 years

Incidence rates for AN are reported to be ten times lower in males, although this is considered an underestimation due to underreporting and underdetection [ 2 ]. Only 16 (20%) of the 78 studies included male participants.

Based on the min/max and standard deviations of the mean provided for duration of illness and BMI, it was clear that many of the articles included subsets of individuals meeting the criteria noted herein for severe and enduring AN. However, as data for those specific individuals were often not delineated, it was not possible to determine how the study conclusions may have differed for said subgroups. For example, the mean duration of illness reported by Hernández et al. [ 75 ] for the AN restricting type (AN-R) subgroup was 4.03 (4.44 SD) years, indicating that at least some of the participants met the duration criteria.

Nevertheless, there were examples of results being assessed against some measures of severity, including duration. The Booij et al. study [ 76 ] AN-R group participant duration of illness was 54.9 (30 SD) months; range: 12–84. They specifically assessed methylation against the cumulative duration of illness and observed associations between duration and methylation levels at 142 probes. The mean duration of illness in the AN-R group in the Steiger et al. study [ 77 ] was 96.00 ± 98.91 (12–456) months. They also assessed duration and found an association between chronicity of illness and methylation status at 64 probes mapping to 55 genes.

Other authors evaluated genetic correlation with the severity of various psychological assessments including quality of life, depression, food behaviors, anxiety, and obsessiveness [ 75 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ]. For example, Acevedo and colleagues found a correlation between specific single nucleotide polymorphisms (SNPs) of the oxytocin receptor gene ( OXTR ), and increased severity of eating disorder symptoms in those with AN [ 78 ]. A polymorphism in the promotor region of the serotonin transporter gene ( 5-HTTLPR ), previously associated with stress and depression [ 91 ], may impact depression and long-term outcomes in those with AN [ 79 ]. Research also suggests a possible correlation between specific haplotypes of the DHEA-producing enzyme cytochrome P450 CYP17A [ 81 ] and the C861 allele of the serotonin receptor 1Dβ gene ( HTR1B ) and severity of anxiety in those with AN.

An example of potential utility in assessing the severe and enduring AN phenotype and the need for larger studies and more funding is the 2022 study by Johansson et al. [ 50 ] evaluating polygenic association with AN severity and long-term outcomes. Here, the authors delineated severe and enduring AN criteria, including duration of illness, clinical impairment, BMI, and having undergone at least one previous treatment attempt. They also specified requirements for the AN subtype, thereby narrowing the population. The study, which included 2843 participants followed for up to 16 years (mean: 5.3 years), provided evidence supporting the possible clinical utility of PGSs for assessing eating disorder risk but also noted the need for larger studies and sample sizes to increase statistical power.

In summary, based on the literature reviewed, genetic studies of AN continue to focus largely, but not exclusively, on younger female participants with shorter durations of illness. These findings are not surprising given that the majority of those diagnosed with AN are female, the lack of clearly defined criteria for severe and enduring AN and the need for large numbers of participants to assess significance in genetics research.

Attempts to provide criteria for labeling those with severe mental illness as chronic or treatment-resistant need to be executed with care, as has been critically reviewed for illnesses such as schizophrenia and depression [ 92 , 93 ]. Care should also be taken when defining criteria for severity of AN, which has a higher mortality rate than depression or schizophrenia [ 94 ]. However, not defining AN severity more clearly and not focusing on a more severe and enduring phenotype in research may decrease the likelihood of identifying the possible underlying biological etiology of AN. As noted by Wonderlich et al. [ 20 ] and responding commentaries by Dalle Grave [ 95 ], Wildes [ 96 ], and McIntosh [ 97 ], a lack of consensus and studies specifically targeting those with severe and enduring AN has resulted in patients being subjected to repetitive employment of largely ineffective treatment strategies resulting in a sense of hopelessness and shame and increasing the risk of suicide [ 98 ]. This review of the literature found that a duration of illness ≥7 years and an unsuccessful response to previous evidence-based treatment were the most common inclusion criteria employed, as were various measures of psychological and physical severity.

AN was once thought to be primarily caused by dysfunctional family dynamics and social and cultural pressures [ 99 ]. We now have evidence that genetics plays a significant role in its etiology. In recent years, there has been an evidence-based push to reconceptualize AN as a metabopsychiatric disorder [ 7 ]. Functional magnetic resonance imaging (fMRI) continues to provide data on the functioning of the brains of those with AN [ 100 ]. The use of large-scale GWAS and genome-wide methylation studies has been gradually revealing the interplay between genetics and environment in AN etiology and persistence, and genetic correlations with other psychiatric disorders [ 16 , 101 , 102 ]. These are all positive advances; however, as evidenced by the individuals included in these studies, female teens and young adults with shorter durations of illness appear to be the primary participants.

Historically, males have been underrepresented in AN research [ 103 ]. Until 2013, the DSM listed amenorrhea as a criterion for AN, thereby reinforcing the notion that AN affects only females [ 61 ]. According to the literature reviewed, males continue to be underrepresented in AN research.

The challenge of recruiting participants for inclusion in large-scale genetic studies of AN is significant. Of the indicated criteria, the most challenging for researchers to assess is the lack of response to prior evidence-based treatment. Most of the treatments described as evidence-based are not administered according to a defined protocol, making retrospective assessment nearly impossible. Furthermore, those with more severe symptoms of longer duration are often treated in a plethora of settings over many years.

For many of the publications, the data indicate that there were participants meeting the criteria defined in the first aim. However, as these individuals were not assessed as a group, it was not possible to determine whether outcomes for this subset may have differed from those with a less severe presentation. The purpose of the publications that either did not perform these assessments or did not report them in their studies was not to delineate this level of detail, so their absence is understandable. One of the reasons for this may be the small number of individuals meeting the criteria for severe and enduring AN, coupled with the need for a large enough “n” to provide any meaningful statistical assessment, which in turn points back to the need for larger studies and additional funding.

Nevertheless, several studies made concerted efforts to focus on a defined severe and enduring phenotype. For example, Kushima et al. [ 74 ] limited their study cohort to those reporting a lifetime lowest BMI < 15 kg/m 2 , with the median for included participants reported as 11.3 kg/m 2 , and a mean age of 37.9 years. The authors specifically stated that they focused on the “severe subgroup of patients because patients with severe symptoms or treatment-resistance are more likely to carry rare deleterious variants of large effect”, citing a schizophrenia study [ 104 ] as support.

The ultimate goal of AN research is to identify contributing factors to the manifestation and intractability of the disease and, in turn, develop superior evidence-based treatments tailored to the patient. Will next generation sequencing gene panels help in the diagnosis of AN [ 105 ]? Kushima et al. [ 74 ] suggested that rare copy number variants associated with neurodevelopmental disorders may correlate with more severe eating disorder subtypes. Is it possible to identify those at higher risk of developing severe and enduring illness earlier and in turn treat those patients based on their specific genetic and environmental circumstances instead of employing generic therapy that may work for most patients with eating disorders but is less effective for those in this cohort? Can artificial intelligence be employed to better identify risk in individuals with AN [ 106 ]? Will we one day regularly employ genetic testing and pharmacogenetics in treating mental illness, including AN [ 107 , 108 ]? Several international projects, including ANGI and the Comprehensive Risk Evaluation for Anorexia Nervosa in Twins (CREAT) are attempting to answer these questions and many more [ 109 , 110 ]. Although these projects do not focus specifically on the severe and enduring phenotype, the availability of in-depth participant health and demographic information paired with genetic analysis should allow for studies of these subsets.

The criteria for evaluating the severity and intractability of AN are evolving, as is the understanding of the disorder. The purpose of a scoping review is to map the literature on an evolving topic and to identify gaps. As such, unlike a systematic review, this review does not attempt to assess the quality of the research conducted, but rather the inclusiveness of study participants. The authors do not attempt to define the severe and enduring phenotype or suggest how the research community should create consensus on the definition. However, by assessing the current literature, we highlight the gaps between the intent to focus on those with severe and enduring AN and the inclusion of this group in published research.

Conclusion and future directions

In conclusion, this review provides an overview of the currently used criteria employed by the research community to define the severity of AN and assesses the last decade of genetics research for the inclusion of study participants meeting these criteria. We found that the following combination of assessments and criteria was used most often in the literature to define AN severity and intractability:

Illness duration of ≥ 7 years.

lack of positive response to at least two previous evidence-based treatments.

A BMI meeting the DSM-5 criteria for extreme AN.

An assessment of psychological and/or behavioral severity indicating a significant impact on quality of life.

We also found, especially in recent years, that there has been an attempt to better define severe and enduring AN in hopes of identifying patients, tailoring treatment, and improving outcomes. However, although a small subset of genetic studies reviewed specifically attempted to focus on a severe and enduring phenotype, there was a lack of aligned defining criteria. Furthermore, there is a continued focus on younger females with shorter disease durations.

Those with AN are often stigmatized, and their shame is amplified by the perception that AN is voluntary or even a lifestyle choice [ 111 , 112 , 113 ]. Those with severe and long-lasting illness are less likely to respond to currently available treatment modalities and have higher levels of mortality [ 20 ]. However, they also represent a subgroup of individuals for which genetic findings may be especially helpful [ 74 ]. Therefore, it is suggested that future genetics studies make a concerted effort to include older participants, those with longer illness durations, and those whose quality of life is most significantly impacted. It is also critically important that more objective, empirically based techniques, such as biomarker and brain structure and function analysis, be developed to more definitively classify the severe and enduring phenotype, which to this point has primarily been categorized through subjective means [ 32 , 60 , 96 , 114 ]. There has been considerable effort in recent years to expand the definition of AN in hopes of being more inclusive and identifying those who may benefit from treatment. However, although expansion has increased the sample size for genetic studies, it could be that focusing on those with longer-lasting and more severe symptomology, even though this is a much smaller group of those with AN, would provide a better chance of identifying the genetic etiology of the disorder. Recent advances have left us far better equipped to make significant progress in developing evidence-based treatments for those with severe and enduring AN. However, these advances require the inclusion of this subgroup in both research and practice.

Limitations

One limitation of the current review is that due to the wide range of similar terminology used to refer to a severe and enduring AN phenotype in the published literature, the searches performed may have left out pertinent articles and viewpoints. Furthermore, although comprehensive for the three electronic databases, the literature search did not include gray literature; thus, information from sources such as dissertations may have been missed.

Data availability

No datasets were generated or analysed during the current study.

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The authors would like to thank Dr. Michael Lutter for his valuable insight and review of the paper.

No funding resources were used in the creation of this review. This work was performed in support of S. Ramsay’s Healthcare Genetics and Genomics doctoral dissertation.

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Ramsay, S., Allison, K., Temples, H.S. et al. Inclusion of the severe and enduring anorexia nervosa phenotype in genetics research: a scoping review. J Eat Disord 12 , 53 (2024). https://doi.org/10.1186/s40337-024-01009-9

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An NIH Genetics Study Targets a Long-Standing Challenge: Diversity

In his  2015 State of the Union  address,  President Barack  Obama  announced  a precision medicine initiative that would later be known as the  All of Us  program. The research, now well underway at the  National Institutes of Health , aims to analyze the  DNA  of at least 1 million people across the United States to build a diverse health database.

The key word there is “diverse.” So far,  the program has collected  more than 560,000 DNA samples, and nearly half of participants identify as being part of a racial or ethnic minority group.

NIH researchers strategically partnered with community health centers, faith-based groups, and Black fraternities and sororities to recruit people who have been historically underrepresented in biomedical research.

“We are actually looking to overrepresent” these previously marginalized groups, explained  Martin Mendoza , director of health equity for All of Us, which will continue to enroll participants through at least 2026, when researchers intend to evaluate the next phases of the project.

Their success to date is remarkable for a few reasons.  Participation in biomedical research  is typically low in diversity. And when it comes to genetics research specifically, diversity has been nearly nonexistent.

Since the completion more than 20 years ago of the  Human Genome Project , which mapped most human genes for the first time, nearly 90 percent of genomics studies have been conducted using DNA from participants of European descent,  research shows .

Humans of all races and ethnicities are 99 percent genetically identical. But even small differences in our DNA can have a profound impact on our health.

Here’s an example: A few years ago,  researchers found  that some Black patients had been misdiagnosed with a potentially fatal heart condition called  hypertrophic cardiomyopathy  because they’d tested positive for genetic variants that were thought to be harmful. But it turns out the variants, more common among  Black Americans  than among  White Americans , are likely harmless. The diagnosis, though, is life-altering — patients with hypertrophic cardiomyopathy have traditionally been discouraged from competing in sports, for example.

Such misdiagnoses can be avoided if “even modest numbers of people from diverse populations are included in sequence databases,” NIH wrote.

Easier said than done. A genetics research project underway in  South Carolina  called  In Our DNA SC   is struggling to recruit enough Black participants . The scientists behind the project said two years ago they aimed to collect samples reflecting the diversity of the state, where 27 percent of residents identify as Black or African American.

“We’d like to be a lot more diverse,” said  Daniel Judge , principal investigator for the study and a cardiovascular genetics specialist at the  Medical University of South Carolina .

To date, only about 12 percent of participants who provided socio-demographic data identify as Black. An additional 5 percent identify as belonging to another racial minority.

This article is not available for syndication due to republishing restrictions. If you have questions about the availability of this or other content for republication, please contact [email protected] .

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By Lauren Sausser May 7, 2024

In his  2015 State of the Union  address,  President Barack  Obama  announced  a precision medicine initiative that would later be known as the  All of Us  program. The research, now well underway at the  National Institutes of Health , aims to analyze the  DNA  of at least 1 million people across the United States to build a diverse health database.

The key word there is “diverse.” So far,  the program has collected  more than 560,000 DNA samples, and nearly half of participants identify as being part of a racial or ethnic minority group.

“We are actually looking to overrepresent” these previously marginalized groups, explained  Martin Mendoza , director of health equity for All of Us, which will continue to enroll participants through at least 2026, when researchers intend to evaluate the next phases of the project.

Their success to date is remarkable for a few reasons.  Participation in biomedical research  is typically low in diversity. And when it comes to genetics research specifically, diversity has been nearly nonexistent.

Here’s an example: A few years ago,  researchers found  that some Black patients had been misdiagnosed with a potentially fatal heart condition called  hypertrophic cardiomyopathy  because they’d tested positive for genetic variants that were thought to be harmful. But it turns out the variants, more common among  Black Americans  than among  White Americans , are likely harmless. The diagnosis, though, is life-altering — patients with hypertrophic cardiomyopathy have traditionally been discouraged from competing in sports, for example.

Such misdiagnoses can be avoided if “even modest numbers of people from diverse populations are included in sequence databases,” NIH wrote.

Easier said than done. A genetics research project underway in  South Carolina  called  In Our DNA SC   is struggling to recruit enough Black participants . The scientists behind the project said two years ago they aimed to collect samples reflecting the diversity of the state, where 27 percent of residents identify as Black or African American.

“We’d like to be a lot more diverse,” said  Daniel Judge , principal investigator for the study and a cardiovascular genetics specialist at the  Medical University of South Carolina .

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A gene long thought to just raise the risk for Alzheimer’s may cause some cases

FILE - A section of a human brain with Alzheimer’s disease is displayed at the Museum of Neuroanatomy at the University at Buffalo, in Buffalo, N.Y., Oct. 7, 2003. A long-feared gene appears to do more than raise people’s risk of Alzheimer’s: Inheriting two copies can cause the mind-robbing disease, according to research published in the journal Nature Medicine on Monday, May 6, 2024. (AP Photo/David Duprey, File)

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WASHINGTON (AP) — For the first time, researchers have identified a genetic form of late-in-life Alzheimer’s disease — in people who inherit two copies of a worrisome gene.

Scientists have long known a gene called APOE4 is one of many things that can increase people’s risk for Alzheimer’s, including simply getting older. The vast majority of Alzheimer’s cases occur after age 65. But research published Monday suggests that for people who carry not one but two copies of the gene, it’s more than a risk factor, it’s an underlying cause of the mind-robbing disease.

The findings mark a distinction with “profound implications,” said Dr. Juan Fortea, who led the study the Sant Pau Research Institute in Barcelona, Spain.

Among them: Symptoms can begin seven to 10 years sooner than in other older adults who develop Alzheimer’s.

An estimated 15% of Alzheimer’s patients carry two copies of APOE4, meaning those cases “can be tracked back to a cause and the cause is in the genes,” Fortea said. Until now, genetic forms of Alzheimer’s were thought to be only types that strike at much younger ages and account for less than 1% of all cases.

Scientists say the research makes it critical to develop treatments that target the APOE4 gene. Some doctors won’t offer the only drug that has been shown to modestly slow the disease, Leqembi, to people with the gene pair because they’re especially prone to a dangerous side effect, said Dr. Reisa Sperling, a study coauthor at Harvard-affiliated Brigham and Women’s Hospital in Boston.

Sperling hunts ways to prevent or at least delay Alzheimer’s and “this data for me says wow, what an important group to be able to go after before they become symptomatic.”

But the news doesn’t mean people should race for a gene test. “It’s important not to scare everyone who has a family history” of Alzheimer’s because this gene duo isn’t behind most cases, she told The Associated Press.

HOW DO GENETICS AFFECT ALZHEIMER’S?

More than 6 million Americans, and millions more worldwide, have Alzheimer’s. A handful of genes are known to cause rare “early-onset” forms, mutations passed through families that trigger symptoms unusually young, by age 50. Some cases also are linked to Down syndrome.

But Alzheimer’s most commonly strikes after 65, especially in the late 70s to 80s, and the APOE gene – which also affects how the body handles fats -- was long known to play some role. There are three main varieties. Most people carry the APOE3 variant that appears to neither increase nor decrease Alzheimer’s risk. Some carry APOE2, which provides some protection against Alzheimer’s.

APOE4 has long been labeled the biggest genetic risk factor for late-in-life Alzheimer’s, with two copies risker than one. About 2% of the global population is estimated to have inherited a copy from each parent.

RESEARCH POINTS TO A CAUSE FOR A SUBSET OF ALZHEIMER’S

To better understand the gene’s role, Fortea’s team used data from 3,297 brains donated for research and from over 10,000 people in U.S. and European Alzheimer’s studies. They examined symptoms and early hallmarks of Alzheimer’s such as sticky amyloid in the brain.

People with two APOE4 copies were accumulating more amyloid at age 55 than those with just one copy or the “neutral” APOE3 gene variety, they reported in the journal Nature Medicine. By age 65, brain scans showed significant plaque buildup in nearly three-quarters of those double carriers – who also were more likely to have initial Alzheimer’s symptoms around that age rather than in the 70s or 80s.

Fortea said the disease’s underlying biology was remarkably similar to young inherited types.

It appears more like “a familial form of Alzheimer’s,” said Dr. Eliezer Masliah of the National Institute on Aging. “It is not just a risk factor.”

Importantly, not everyone with two APOE4 genes develops Alzheimer’s symptoms and researchers need to learn why, Sperling cautioned.

“It’s not quite destiny,” she said.

HOW THE NEW FINDINGS MAY AFFECT ALZHEIMER’S RESEARCH AND TREATMENT

The drug Leqembi works by clearing away some sticky amyloid but Sperling said it’s not clear if carriers of two APOE4 genes benefit because they have such a high risk of a side effect from the drug – dangerous brain swelling and bleeding. One research question is whether they’d do better starting such drugs sooner than other people.

Masliah said other research aims to develop gene therapy or drugs to specifically target APOE4. He said it’s also crucial to understand APOE4’s effects in diverse populations since it’s been studied mostly in white people of European ancestry.

As for gene tests, for now they’re typically used only to evaluate if someone’s a candidate for Leqembi or for people enrolling in Alzheimer’s research – especially studies of possible ways to prevent the disease. Sperling said the people most likely to carry two APOE4 genes had parents who both got Alzheimer’s relatively early, in their 60s rather than 80s.

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

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Study Suggests Genetics as a Cause, Not Just a Risk, for Some Alzheimer’s

People with two copies of the gene variant APOE4 are almost certain to get Alzheimer’s, say researchers, who proposed a framework under which such patients could be diagnosed years before symptoms.

By Pam Belluck

Scientists are proposing a new way of understanding the genetics of Alzheimer’s that would mean that up to a fifth of patients would be considered to have a genetically caused form of the disease.

Currently, the vast majority of Alzheimer’s cases do not have a clearly identified cause. The new designation, proposed in a study published Monday, could broaden the scope of efforts to develop treatments, including gene therapy, and affect the design of clinical trials.

It could also mean that hundreds of thousands of people in the United States alone could, if they chose, receive a diagnosis of Alzheimer’s before developing any symptoms of cognitive decline, although there currently are no treatments for people at that stage.

The new classification would make this type of Alzheimer’s one of the most common genetic disorders in the world, medical experts said.

“This reconceptualization that we’re proposing affects not a small minority of people,” said Dr. Juan Fortea, an author of the study and the director of the Sant Pau Memory Unit in Barcelona, Spain. “Sometimes we say that we don’t know the cause of Alzheimer’s disease,” but, he said, this would mean that about 15 to 20 percent of cases “can be tracked back to a cause, and the cause is in the genes.”

The idea involves a gene variant called APOE4. Scientists have long known that inheriting one copy of the variant increases the risk of developing Alzheimer’s, and that people with two copies, inherited from each parent, have vastly increased risk.

The new study , published in the journal Nature Medicine, analyzed data from over 500 people with two copies of APOE4, a significantly larger pool than in previous studies. The researchers found that almost all of those patients developed the biological pathology of Alzheimer’s, and the authors say that two copies of APOE4 should now be considered a cause of Alzheimer’s — not simply a risk factor.

The patients also developed Alzheimer’s pathology relatively young, the study found. By age 55, over 95 percent had biological markers associated with the disease. By 65, almost all had abnormal levels of a protein called amyloid that forms plaques in the brain, a hallmark of Alzheimer’s. And many started developing symptoms of cognitive decline at age 65, younger than most people without the APOE4 variant.

“The critical thing is that these individuals are often symptomatic 10 years earlier than other forms of Alzheimer’s disease,” said Dr. Reisa Sperling, a neurologist at Mass General Brigham in Boston and an author of the study.

She added, “By the time they are picked up and clinically diagnosed, because they’re often younger, they have more pathology.”

People with two copies, known as APOE4 homozygotes, make up 2 to 3 percent of the general population, but are an estimated 15 to 20 percent of people with Alzheimer’s dementia, experts said. People with one copy make up about 15 to 25 percent of the general population, and about 50 percent of Alzheimer’s dementia patients.

The most common variant is called APOE3, which seems to have a neutral effect on Alzheimer’s risk. About 75 percent of the general population has one copy of APOE3, and more than half of the general population has two copies.

Alzheimer’s experts not involved in the study said classifying the two-copy condition as genetically determined Alzheimer’s could have significant implications, including encouraging drug development beyond the field’s recent major focus on treatments that target and reduce amyloid.

Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai in New York, who was not involved in the study, said that patients with two copies of APOE4 faced much higher safety risks from anti-amyloid drugs.

When the Food and Drug Administration approved the anti-amyloid drug Leqembi last year, it required a black-box warning on the label saying that the medication can cause “serious and life-threatening events” such as swelling and bleeding in the brain, especially for people with two copies of APOE4. Some treatment centers decided not to offer Leqembi, an intravenous infusion, to such patients.

Dr. Gandy and other experts said that classifying these patients as having a distinct genetic form of Alzheimer’s would galvanize interest in developing drugs that are safe and effective for them and add urgency to current efforts to prevent cognitive decline in people who do not yet have symptoms.

“Rather than say we have nothing for you, let’s look for a trial,” Dr. Gandy said, adding that such patients should be included in trials at younger ages, given how early their pathology starts.

Besides trying to develop drugs, some researchers are exploring gene editing to transform APOE4 into a variant called APOE2, which appears to protect against Alzheimer’s. Another gene-therapy approach being studied involves injecting APOE2 into patients’ brains.

The new study had some limitations, including a lack of diversity that might make the findings less generalizable. Most patients in the study had European ancestry. While two copies of APOE4 also greatly increase Alzheimer’s risk in other ethnicities, the risk levels differ, said Dr. Michael Greicius, a neurologist at Stanford University School of Medicine who was not involved in the research.

“One important argument against their interpretation is that the risk of Alzheimer’s disease in APOE4 homozygotes varies substantially across different genetic ancestries,” said Dr. Greicius, who cowrote a study that found that white people with two copies of APOE4 had 13 times the risk of white people with two copies of APOE3, while Black people with two copies of APOE4 had 6.5 times the risk of Black people with two copies of APOE3.

“This has critical implications when counseling patients about their ancestry-informed genetic risk for Alzheimer’s disease,” he said, “and it also speaks to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk.”

Under the current genetic understanding of Alzheimer’s, less than 2 percent of cases are considered genetically caused. Some of those patients inherited a mutation in one of three genes and can develop symptoms as early as their 30s or 40s. Others are people with Down syndrome, who have three copies of a chromosome containing a protein that often leads to what is called Down syndrome-associated Alzheimer’s disease .

Dr. Sperling said the genetic alterations in those cases are believed to fuel buildup of amyloid, while APOE4 is believed to interfere with clearing amyloid buildup.

Under the researchers’ proposal, having one copy of APOE4 would continue to be considered a risk factor, not enough to cause Alzheimer’s, Dr. Fortea said. It is unusual for diseases to follow that genetic pattern, called “semidominance,” with two copies of a variant causing the disease, but one copy only increasing risk, experts said.

The new recommendation will prompt questions about whether people should get tested to determine if they have the APOE4 variant.

Dr. Greicius said that until there were treatments for people with two copies of APOE4 or trials of therapies to prevent them from developing dementia, “My recommendation is if you don’t have symptoms, you should definitely not figure out your APOE status.”

He added, “It will only cause grief at this point.”

Finding ways to help these patients cannot come soon enough, Dr. Sperling said, adding, “These individuals are desperate, they’ve seen it in both of their parents often and really need therapies.”

Pam Belluck is a health and science reporter, covering a range of subjects, including reproductive health, long Covid, brain science, neurological disorders, mental health and genetics. More about Pam Belluck

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