Gender difference accounts for major psychiatric disorders

According to an analysis of sex variations in the genetics of bipolar disorder, schizophrenia, and major depressive disorders, while there is a significant genetic overlap between females and males, there are visible sex-dependent variations in how genes associated with the central nervous system, blood vessels, and immune system affect individuals with these disorders.

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The results provided by a multinational consortium of psychiatric researchers, including scientists and a senior author from Massachusetts General Hospital (MGH), may lead to better therapies for major psychiatric disorders. The findings were published in the Biological Psychiatry journal.

The discoveries were made possible through the collaboration of over 100 research teams and scientists, who sifted through the genomes of 19,924 persons affected by bipolar disorder, 33,403 people with schizophrenia, 32,408 people with major depressive disorder, and also 109,946 controls (individuals without any of these diagnoses).

The aim of the researchers was to find out why these major psychiatric disorders varied between men and women. Women, for instance, have a considerably higher risk of major depressive disorder, while men have a substantially higher risk of schizophrenia. The risk of bipolar disorder is roughly the same for both sexes, but the onset, course, and prognosis of the disease vary significantly 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.”

Jill M. Goldstein, PhD, Study Senior Author and Founder, Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital

Goldstein is also the executive director of the Innovation Center on Sex Differences in Medicine (ICON).

Goldstein and collaborators looked for clues in the form of single nucleotide polymorphisms or SNPs (pronounced as ‘‘snips”) where a single DNA “letter’ (nucleotide) differs from one person to another and between men and women.

There are sex differences in the frequency of chronic diseases and cancers as well. It’s pervasive. 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.”

Jill M. Goldstein, PhD, Study Senior Author and Founder, Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital

Goldstein is also a professor of Psychiatry and Medicine at Harvard Medical School.

By leveraging large psychiatric databases, the team was able to show that the interactions of certain genes with sex, in addition to the effects of sex hormones, like testosterone or estradiol, affect the risks for bipolar disorder, schizophrenia, and major depressive disorders.

For instance, the researchers observed the interactions with depression, schizophrenia, as well as sex in genes that control the production of vascular endothelial growth factor—a protein that supports 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.”

Jill M. Goldstein, PhD, Study Senior Author and Founder, Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital

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,” Goldstein added.

The researchers emphasized that while the exact causes of the diseases studied by them are still vague, “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,” concluded Goldstein.

Source:
Journal reference:

Blokland, G. A. M., et al. (2021) Sex-Dependent Shared and Non-Shared Genetic Architecture, Across Mood and Psychotic Disorders. Biological Psychiatry. doi.org/10.1016/j.biopsych.2021.02.972.

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