Genetic study identifies gender-dependent differences in major psychiatric disorders

An analysis of gender differences in the genetics of schizophrenia, bipolar disorder, and major depressive disorder indicates that while there is substantial genetic overlap between males and females, there are notable gender differences in how genes are linked 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 lead author from Massachusetts General Hospital (MGH), could stimulate better treatments for major psychiatric disorders. They are published in the journal Biological Psychiatry.

The results were only made possible through the cooperation of more than 100 researchers 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 these diagnoses).

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

We are in the age of big data and we are researching disease-associated genes to identify genotype-associated drug targets, in order to develop more effective treatments for this disease that may differ by gender. “

Jill M. Goldstein, PhD, Senior Author, Founder and Executive Director of the Gender Differences in Medicine Innovation Center (ICON) at MGH

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

“There are also gender differences in the frequency of chronic disease and cancer. It’s ubiquitous,” says Goldstein, who is also a professor of psychiatry and medicine at Harvard Medical School. “But medicine, essentially, has been built on models of male health and male animals. We need to develop our precision medicine models that incorporate the effect of sex.”

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

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

“My lab studies the substantial co-occurrence of depression and cardiovascular disease. It turns out that depression and schizophrenia have a very high co-occurrence with cardiovascular disease. We believe that there are common causes between psychiatric and cardiovascular disease. that are not due to the effects of the drugs, “she says.” 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 discovery of depression of sex differences in a gene controlling vascular endothelial growth factor. “

The investigators point out 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 interactions with sex. Dissecting the impact of gender, genes, and pathophysiology will identify potential targets for gender-dependent or gender-specific therapeutic interventions, creating more effective therapies for men and women, ”she says.

Source:

Massachusetts General Hospital

Journal reference:

Blokland, GAM, et al. (2021) Shared and non-shared gender-dependent genetic architecture, through mood disorders and psychotic disorders. Biological Psychiatry. doi.org/10.1016/j.biopsych.2021.02.972.

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