Autism may stem from a different — and larger — set of genetic mutations in women than it does in men, according to a new study1.
The findings support a growing body of evidence suggesting that women require a bigger genetic hit than men do to have conditions that affect brain development, including autism.
Autism affects about four men for every one woman, according to a comprehensive analysis from 2017. The cause of this sex bias is an “outstanding question in the field,” says Tychele Turner, assistant professor of genetics at Washington University in St. Louis, Missouri, who led the new work.
Researchers used to have to pool men and women to amass the sample sizes needed to identify genes that may contribute to a condition. But today they have access to tens of thousands of genetic samples — enough to look at each sex independently, Turner says.
“We thought: Now that all that data exists, could we go back and begin to ask questions about the difference in males and females?” she says.
Turner’s team linked 22 genes to conditions of brain development in a sample of women versus 18 genes in twice as many men.
The findings support the idea that women can sustain a larger genetic hit than men without having autism, a phenomenon called the ‘female protective effect,’ says Donna Werling, assistant professor of genetics at the University of Wisconsin-Madison, who was not involved in the work. But the mechanisms that might protect women are a mystery.
Investigating how autism genes differ by sex will be key to understanding the mechanisms “for either female protection or male risk or vulnerability,” Werling says.
Turner’s team used genetic data from denovo-db, a database that contains information on people who have brain developmental conditions and carry de novo variants — those not inherited from parents. These conditions are linked to genes that have a high burden of de novo mutations2.
The researchers combed the genomes of 2,133 women and girls, and 4,641 men and boys for genes with more de novo mutations than would be expected to occur by chance. They found 17 such genes exclusively in females, 18 exclusively in males and 19 in both sexes.
They searched for these 54 mutations in 18,778 genomes — including 8,399 from girls and women — taken from a database called GeneDx. This analysis whittled down the number of genes tied to these conditions to 7 in females, 3 in males and 15 in both groups.
The 15 genes that affect both sexes tend to be expressed in neurons, whereas the 10 that preferentially affect one sex are expressed across distinct cell types in the cerebral cortex. Turner declines to speculate about this difference, saying only that it is “interesting.”
Of the 25 genes overall, 22 are involved in many of the same pathways — for instance, those that govern how DNA gets transcribed into RNA — which suggests that they regulate other genes. The study was published in November in The American Journal of Human Genetics.
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