Sex, Genes and Vulnerability

Researchers pinpoint genes behind sex biases in autoimmune disorders, schizophrenia

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Get a two-minute summary of the study findings from first author Nolan Kamitaki.

Some diseases exhibit a clear sex bias, occurring more often, hitting harder or eliciting different symptoms in men or women.

For instance, the autoimmune conditions lupus and Sjögren's syndrome affect nine times more women than men, while schizophrenia affects more men and tends to cause more severe symptoms than in women.

Likewise, early reports suggest that despite similar rates of infection, men are dying from COVID-19 more often than women, as happened during previous outbreaks of the related diseases SARS and MERS.

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For decades, scientists have tried to pinpoint why some diseases have an unexpected sex bias. Behavior can play a role, but that explains only a piece of the puzzle. Hormones are commonly invoked, but how exactly they contribute to the disparity is unclear. As for genes, few, if any, answers have been found on the X and Y sex chromosomes for most diseases.

Now, work led by researchers in the Blavatnik Institute at Harvard Medical School and at the Broad Institute of MIT and Harvard provides a clear genetic explanation behind the sex bias observed in some of these diseases.

The team's findings, reported May 11 in Nature, suggest that greater abundance of an immune-related protein in men protects against lupus and Sjögren's but heightens vulnerability to schizophrenia.

The protein, called complement component 4 (C4) and produced by the C4 gene, tags cellular debris for prompt removal by immune cells.

The team's key findings:

  • People with the most C4 genes were seven times less likely to develop systemic lupus erythematosus, an autoimmune condition that can range from mild to life-threatening, and 16 times less likely to develop primary Sjögren's syndrome, a systemic autoimmune syndrome characterized by dry eyes and dry mouth, than those with the fewest C4 genes. Conversely, those with the most C4 genes were 1.6 times more likely to develop the neuropsychiatric condition schizophrenia.
  • Even in people with similar complement gene profiles, the genes produce more protein in men than in women, further skewing disease susceptibility and protection.

"Sex acts as a lens that magnifies the effects of genetic variation," said the study's first author, Nolan Kamitaki, research associate in genetics in the lab of Steven McCarroll at HMS and the Broad.

"We all know about illnesses that either women or men get a lot more, but we've had no idea why," said Steven McCarroll, the Dorothy and Milton Flier Professor of Biomedical Science and Genetics at HMS and director of genomic neurobiology at the Stanley Center for Psychiatric Research at the Broad. "This work is exciting because it gives us one of our first handles on the biology."

McCarroll is co-senior author of the study with Timothy Vyse of King's College London.

Although C4 variation appears to contribute powerfully to disease risk, it is only one among many genetic and environmental factors that influence disease development.

The study's results are informing the ongoing development of drugs that modulate the complement system, the authors said.

"For example, researchers will need to make sure that drugs that tone down the complement system do not unintentionally increase risk for autoimmune disease," said McCarroll. "Scientists will also need to consider the possibility that such drugs may be differentially helpful in male and female patients."

On a broader level, the work offers a more solid foundation for understanding sex variation in disease than has been available before.

"It's helpful to be able to think about sex-biased disease biology in terms of specific molecules, beyond vague references to 'hormones,'" McCarroll said. "We now realize that the complement system shapes vulnerability for a wide variety of illnesses."

Cell sweeper

In 2016, researchers led by Aswin Sekar, a former McCarroll lab member who is a co-author of the new study, made international headlines when they revealed that specific C4 gene variants underlie the largest common genetic risk factor for developing schizophrenia.

The new work suggests that C4 genes confer both an advantage and disadvantage to carriers, much as the gene variant that causes sickle cell disease also protects people against malaria.

"C4 gene variants come with this yin and yang of heightened and reduced vulnerability in different organ systems," said McCarroll.

Sex acts as a lens that magnifies the effects of genetic variation.
Nolan Kamitaki
HMS research associate in genetics
There were all these medical hints. Human genetics helps put those hints together.
Steven McCarroll
the Dorothy and Milton Flier Professor of Biomedical Science and Genetics at HMS
It will really help for genetics to expand more strongly beyond European ancestries and learn from genetic variation and ancestries all over the world.
Steven McCarroll