Large-Scale Genome Analysis Identifies Differences by Sex in Major Psychiatric Disorders

Summary: Researchers found that while there are genetic overlaps between the sexes in relation to mental health disorders, there are also sex-specific differences in how genes related to the immune system, central nervous system, and blood vessels affect people with mental health problems.

Source: Mass General

An analysis of sex differences in the genetics of schizophrenia, bipolar disorder and major depressive disorders indicates that while there is substantial genetic overlap between males and females, there are noticeable sex-dependent differences in how genes related to the central nervous system, immune system, and blood vessels affect people with these disorders.

The findings, from a multinational consortium of psychiatric researchers including investigators and a senior author at Massachusetts General Hospital (MGH), could spur better treatments for major psychiatric disorders.

They are published in the journal Biological Psychiatry.

The findings were made possible only through the cooperation of more than 100 investigators and research groups, who combed through the genomes of 33,403 people with schizophrenia, 19,924 with bipolar disorder, and 32,408 with major depressive disorder, as well as 109,946 controls (people without any of these diagnoses).

Their goal was to understand why these major psychiatric disorders differed between the sexes. For example, women have a significantly higher risk for major depressive disorder, whereas the risk for schizophrenia is significantly higher among men. The risk of bipolar disorder is about the same for both women and men, but disease onset, course, and prognosis differ markedly between the two.

“We’re in the era of Big Data, and we’re looking for genes that are associated with illnesses to identify druggable targets associated with the genotype, in order to develop more effective treatments for that illness that may differ by sex,” says senior author Jill M. Goldstein, PhD, founder and executive director of the Innovation Center on Sex Differences in Medicine (ICON) at MGH.

Goldstein and colleagues searched for clues in the form of single nucleotide polymorphisms, or SNPs (“snips”), in which a single DNA “letter” (nucleotide) differs from one person to the next and between sexes.

“There are sex differences in the frequency of chronic diseases and cancers as well. It’s pervasive,” says Goldstein, who is also a professor of Psychiatry and Medicine at Harvard Medical School. “But medicine, essentially, has been built on models of men’s health and male animals. We need to develop our precision medicine models incorporating the effect of sex.”

By taking advantage of large psychiatric databases, the investigators were able to demonstrate that the risks for schizophrenia, bipolar disorder and major depressive disorder are affected by interactions of specific genes with sex, apart from the effects of sex hormones such as estradiol or testosterone.

For example, the investigators found interactions with schizophrenia and depression and sex in genes controlling for the production of vascular endothelial growth factor, a protein that promotes the growth of new blood vessels.

“My lab is studying the substantial co-occurrence of depression and cardiovascular disease. It turns out that both depression and schizophrenia have a very high co-occurrence with cardiovascular disease. We believe there are shared causes between psychiatric and cardiovascular diseases that are not due to the effects of medication,” she says.

This shows the outline of two heads
The risk of bipolar disorder is about the same for both women and men, but disease onset, course, and prognosis differ markedly between the two. Image is in the public domain

“In addition, the co-occurrence of depression and cardiovascular disease is twice as high in women as in men, and this may, in part, be associated with our finding in depression of sex differences in a gene controlling vascular endothelial growth factor.”

The investigators emphasize that although the specific causes of the diseases they studied are still unknown, “our study underscores the importance of designing large-scale genetic studies that have the statistical power to test for interactions with sex. Dissecting the impact of sex, genes, and pathophysiology will identify potential targets for sex-dependent or sex-specific therapeutic interventions creating more effective therapies for both men and women,” she says.

Funding: The analyses were supported by private donor Gwill York, the National Institute of Mental Health and the NIH Office for Research on Women’s Health.

About this genetics and mental health research news

Source: Mass General
Contact: Noah Brown – Mass General
Image: The image is in the public domain

Original Research: Closed access.
Sex-Dependent Shared and Non-Shared Genetic Architecture, Across Mood and Psychotic Disorders” by Jill M. Goldstein et al. Biological Psychiatry


Sex-Dependent Shared and Non-Shared Genetic ArchitectureAcross Mood and Psychotic Disorders


Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.


We conducted the largest to date genome-wide genotype–by–sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH.


Across disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815; p=3.2×10−8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p<1×10−6) for cross-disorder GxS interaction (rs7302529, p=1.6×10−7; rs73033497, p=8.8×10−7; rs7914279, p=6.4×10−7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97×10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282; p=1.5×10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509; p=1.1×10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDR<0.05).


In the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.

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