Just as recent research has shown that the sex of cells used in cellular models can bias studies of neurological disease, new research is showing that men and women also have genetic differences that are linked to their likelihood of developing certain psychotic and mood disorders.
The study, published March 22 in Biological Psychiatry, is the largest genome-wide association study (GWAS) to date—including contributions from more than 100 researchers—to look at the underlying genetic differences between the sexes for insight into why bipolar disorder, schizophrenia, and depression affect men and women differently and at different rates.
The GWAS identified almost a dozen single nucleotide polymorphisms (SNPs) that differed between men and women diagnosed with one of the three disorders. In some instances, a SNP was only linked to disease in one sex, while in other cases the same SNP decreased the likelihood of developing a disorder in one sex while increasing it in the other. The genes harboring these SNPs were linked to vascular, immune, and neuronal development pathways, providing clues about the interplay between cardiovascular and neurological health.
The current research combines data from two international consortia, the Psychiatric Genomics Consortium (PGC) and iPSYCH, both of which aim to tease apart the genetic and environmental factors that affect mental health. Together, the two collections represent a pool of almost 200,000 patients of European ancestry, roughly half of whom have been diagnosed with one of the three disorders.
The Scientist spoke with Jill Goldstein, a clinical neuroscientist at Harvard Medical School and the senior author of the study, about the team’s findings.
The Scientist: You open the paper by pointing out that sex-based differences in the incidence and presentation of certain mood and psychotic disorders are pervasive. How does that most commonly manifest?
Jill Goldstein: If you start at the population level, there are sex differences in the incidence of major psychiatric disorders. For example, in schizophrenia there’s a slightly higher incidence in men than in women, but in major depression and anxiety disorders, the risk is actually two-fold higher in women than in men. The importance is that it’s worldwide, it is not culture-specific, so [scientists] really believe there is a biology to understanding the incidence difference.
There are also sex differences in the expression of these illnesses—their course, their prognosis, their treatment response. So you really want to understand both when asking, what is the impact of sex and gender on understanding these disorders?
My lab studies the biology of sex, so we’ve been focused on sex differences with developmental roots. We’re really interested in how the healthy brain develops differently in males and females and how that gets dysregulated in development, setting the stage for why we see sex differences down the road [in mental illness].
TS: Can you walk me through one or two of the more meaningful SNPs that most intrigued you?
JG: When you do these studies, they’re not getting into the weeds about the biology itself. They’re really just saying that a particular SNP has been associated with something . . . in the past, and now it looks like it is expressed differently in men with a disorder versus women with that disorder. I call them flashlights. They give us clues for where to look next on a more mechanistic level for a deeper dive into understanding their significance.
But the fact that we actually identified some functional SNPs . . . that differed significantly by sex was really a first, and so we’re extremely excited.
We found a SNP in the IDO2 gene. [It’s] an immunoregulatory gene with functions implicated in all three disorders that led to opposing effects in the different disorders. The SNP increased the risk of bipolar disorder in women and decreased the risk in men, but it also decreased the risk of major depression in women and increased the risk in men. We also found some shared things between depression and schizophrenia. With that same genetic SNP, we found a lower risk of depression and schizophrenia in women, but a higher risk in the men.
So there are actually these really interesting opposing effects, and people will say it sounds spurious, but it turns out that these SNPs may relate to the differential risks [for disease] that we see in men and women.
And what was even more exciting was that the pathways that were implicated—vascular pathways and immune pathways—fit with what has been found and mapped by the neurobiology. We study the shared pathophysiology between the brain and the heart, but it turns out that schizophrenia also has a very high comorbidity with cardiovascular disease. I was thrilled to see we actually found these genes with shared sex differences in areas that we’ve been studying.
TS: What happens if scientists don’t account for these differences?
JG: The differences we found are small, but small differences actually tell us really important things about substantial differences in incidence, and also about treatment and response to treatment differences.
We’re living in the day and age of precision medicine, and we want to identify genes that are associated with treatment responses so we can personalize our treatments. It’s absolutely critical, if we’re going to talk about these things, to consider sex and gender. In 2001, for example, eighty percent of adverse drug reactions [occurred in] women. But most studies in neuroscience and in medicine in general involve male animals, so we shouldn’t be surprised that the side effects and drug reactions would be greater in women than in men.
We’re living in the day and age of precision medicine, and we want to identify genes that are associated with treatment responses so we can personalize our treatments.—Jill Goldstein, Harvard Medical School
There are a few instances in which this has changed treatment completely. One is in cardiovascular disease, where it’s primarily treated as a small vessel disease in women and a large vessel disease in men. Before, most of our treatments were developed for large vessel disease and the development of plaques. When these sex-based differences were discovered, it really revolutionized women’s heart health programs.
There are also examples in stroke and in lung cancer, in which brilliant scientists were about to throw a treatment away because it looked like it didn’t work. But it turned out that in lung cancer, for example, they were targeting a mutation [linked to] a form of lung cancer that was more common in women, but they were testing it using male animals.
There are real-life consequences if we do not develop sex-dependent therapeutics, and I think it is critical for precision medicine.
TS: How can scientists start to account for sex-based differences in their research?
JG: One thing to do is to start looking at the functional consequences of these genes now in live people and to really design your study to look for sex effects. Otherwise, you can’t control away a design flaw when testing a complicated variable like sex. You need to design your studies by sex and you need to understand that every cell has a sex. We metabolize drugs differently, we absorb them differently, we eliminate them differently. And there are different pharmacodynamics to these drugs. We need to really understand that, and starting at the genetic level is also really important.
G.A.M. Blokland et al., “Sex-dependent shared and non-shared genetic architecture, across mood and psychotic disorders,” Biol Psychiatry, doi:10.1016/j.biopsych.2021.02.972, 2021.
Editor’s note: This interview was edited for brevity.