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Sex-specific Genetic Effects Across Neuropsychiatric and Behavioral Traits Identified for the First Time

Key findings

  • This study evaluated sex differences within and across 20 neuropsychiatric and behavioral traits using three complementary approaches—estimation of single nucleotide polymorphism (SNP)–based heritability, genetic correlation and heterogeneity analyses
  • SNP-based heritability differed significantly by sex for recurrent major depressive disorder, autism spectrum disorder and schizophrenia; these traits were among those with the largest sample sizes
  • There were moderate-to-high genetic correlations between males and females for nearly all traits
  • There were no significant sex differences in the genetic effects of any individual SNP, but the number of children born was associated with GLB1L2, risk-taking behavior was associated with HFE2 and AGO2, and schizophrenia was associated with SLTM
  • A number of pairs of traits were found to share sex-dependent genetic effects; for example, there were correlations between autism spectrum disorder and attention-deficit hyperactivity disorder and between bipolar disorder and schizophrenia

It's now established that neuropsychiatric and behavioral disorders share a considerable portion of their genetic "architecture" with each other, and the prevalence and presentation of many disorders differ by sex.

Given this evidence, the international Psychiatric Genomics Consortium formed a Sex Differences Cross-Disorder Analysis Group to investigate whether the genetic correlations of neuropsychiatric and behavioral traits are different for males and females. Jill M. Goldstein, PhD, MPH, executive director of the Innovation Center on Sex Differences in Medicine and the Helen T. Moerschner Endowed MGH Research Institute Chair in Women's Health, and Jordan W. Smoller, MD, ScD, director of the Psychiatric and Neurodevelopmental Genetics Unit in the Department of Psychiatry at Massachusetts General Hospital, are two senior members of the group.

In Biological Psychiatry, the group reports that the majority of genetic effects they identified for neuropsychiatric and behavioral traits were similar for men and women, but some were sex-differentiated. Moreover, the group shows for the first time that a portion of sex-differentiated genetic effects are shared across traits.

SNP-based Heritability

The researchers analyzed sex-stratified data on 20 neuropsychiatric and behavioral traits from European-ancestry genome-wide association studies. They calculated that single nucleotide polymorphism (SNP)-based heritability differed significantly by sex for recurrent major depressive disorder (MDDR), autism spectrum disorder (ASD) and schizophrenia. These traits were among those with the largest sample sizes.

For several traits, sex differences could not be assessed because of insufficient power or excessive heterogeneity: post-traumatic stress disorder and MDDR in males and ASD and alcohol dependence in females.

Between-Sex, Within-Trait Genetic Correlations

There were moderate-to-high genetic correlations between males and females for nearly all traits that could be studied. As exceptions, there was a modest degree of heterogeneity between males and females for risk-taking behavior and educational attainment.

Between-Sex, Within-Trait Heterogeneity

No sex differences in the genetic effects of any individual SNP were statistically significant at the genome-wide level. However, several traits had significant sex-differentiated gene associations: the number of children born was associated with GLB1L2, risk-taking behavior was associated with HFE2 and AGO2, and schizophrenia was associated with SLTM.

Shared Sex-Differentiated Effects

In some cases, a sex difference observed at a gene was shared by a pair of traits. For example, there were correlations between ASD and attention-deficit hyperactivity disorder and between bipolar disorder and schizophrenia. All correlations were small or moderate but statistically significant.

Using and extending the same cohort, reported in Biological Psychiatry, Dr. Goldstein and Dr. Smoller found significant sex differences shared and non-shared in the genetic architecture of psychiatric disorders themselves, that is, schizophrenia, bipolar disorder, and major depressive disorder. While there was substantial genetic overlap in these disorders between men and women, there were significant sex-dependent differences in how genes related to the central nervous system, immune system, and vasculature.

Research Implications

Sex differences in the common autosomal genetic architecture of the traits studied here were small and polygenic, and thus contribute one piece of the puzzle in understanding the pronounced sex differences in the prevalence of many psychiatric disorders. Larger samples are needed to detect interaction effects with sex at the individual SNP level for traits, as was conducted for psychiatric disorders in the previous work cited above.

Sex differences in the prevalence of many psychiatric disorders are likely explained by the interplay between genes and environment and may be trait-specific across disorders. Considerably more research is needed to understand these relationships, which is critical for excelerating the development of sex-specific diagnostics and therapeutics.

Learn more about the Psychiatric and Neurodevelopmental Genetics Unit

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