In the largest genome analysis study on mood and psychotic disorders known to date, a multinational team of scientists has scanned approximately 200,000 genomes to show, although there is substantial genetic overlap between the sexes, there exist noticeable sex-dependent differences in how genes related to neuronal development, immune and vascular functions affect patients across three prominent psychiatric disorders: schizophrenia, bipolar disorder, and major depressive disorder.
The findings, published in “‘Sex-Dependent Shared and Non-Shared Genetic Architecture, Across Mood and Psychotic Disorders’” in the journal Biological Psychiatry could spur better treatments for major psychiatric disorders.
This large-scale study is a collaborative effort including more than 100 investigators and research groups, who compared the genomes of 33,403 people with schizophrenia, 19,924 with bipolar disorder, and 32,408 with major depressive disorder, and 109,946 normal subjects (controls).
Women have a higher risk for major depressive disorder while men have a higher risk schizophrenia. 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 sexes. The team aimed to understand why these major psychiatric disorders differ between the sexes.
“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 and professor of psychiatry and medicine at Harvard Medical School.
Single alphabet differences in DNA known as single nucleotide polymorphisms or SNPs (often called ‘snips’) offer clues into differences in the expression of a disease. Therefore, Goldstein and her team focused on SNP analysis in this study.
“There are sex differences in the frequency of chronic diseases and cancers as well. It’s pervasive,” says Goldstein. “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.”
The investigators demonstrate that the risks for schizophrenia, bipolar disorder and major depressive disorder are affected by interactions of specific genes with sex, distinct from the effects of sex hormones such as estradiol or testosterone. This study was based on large datasets available at the Psychiatric Genomics Consortium (PGC) and iPSYCH databases.
The authors emphasize “our study underscores the importance of designing large-scale genetic studies that have the statistical power to test for interactions with sex.”
The team found interactions with schizophrenia and depression and sex in genes controlling the production of vascular endothelial growth factor (VEGF), 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,” Goldstein 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 finding in depression of sex differences in a gene controlling vascular endothelial growth factor.”
Across disorders, the authors detected genome-wide significant SNP-by-sex interaction for a genomic region including the gene NKAIN2 that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. The transcriptional inhibitor SLTM showed a sex difference across disorders. Most significant in schizophrenia, was a genetic region called MOCOS, important in cells that line blood vessels. Pathway enrichment analysis detected significant differences of genes regulating VEGF receptor signaling in major depressive disorder.
The authors believe dissecting the impact of sex, genes, and pathophysiology will identify potential targets for sex-specific therapeutic interventions creating more effective therapies for both men and women.