Genes on the X and Y chromosomes—and especially those on the Y—appear to be associated with autism likelihood, according to a study focused on people who have missing or extra sex chromosomes. The findings add to the ongoing debate about whether autism’s sex bias reflects a male vulnerability, a female protective effect or other factors.
“The Y chromosome is often left out of genetic discovery studies. We really have not interrogated it in [autism] studies very much,” says Matthew Oetjens, assistant professor of human genetics at Geisinger Medical Center’s Autism and Developmental Medicine Institute, who led the new work.
There is a clear sex difference in autism prevalence: Men are about four times as likely as women to have a diagnosis. But uncovering the reasons for that discrepancy has proved challenging and contentious. Multiple biological factors may play a role, in addition to social factors—such as the difficult-to-measure gulfs between how boys and girls are taught to behave. Add on the possibility of diagnostic bias and the question starts to look less like a scientific problem and more like a politically toxic Gordian knot.
But there are some threads that researchers can pull to disentangle these effects, as the new study illustrates. People with sex chromosome aneuploidies—or unusual combinations of sex chromosomes, such as XXY in those with Klinefelter syndrome or a single X in Turner syndrome—provide a unique opportunity to examine how adding or taking away chromosomes can affect biology and behavior.
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revious studies noted high rates of autism in people with sex chromosome aneuploidies, but those analyses were subject to ascertainment bias; perhaps those people found out about their aneuploidies only after seeking support for their neurodevelopmental conditions.To mitigate that bias, Oetjens and his colleagues looked for people with aneuploidies in an autism dataset called SPARK. (The SPARK study is funded by the Simons Foundation, The Transmitter’s parent organization.) Because aneuploidies are rare, this strategy demanded an enormous volume of data—and patience, Oetjens says. “When the SPARK cohort got large enough, that really opened up the avenue to do this.”
Both the SPARK dataset and a control dataset, Geisinger’s MyCode, included participants with sex chromosome aneuploidies, notably Klinefelter, Turner, Triple X (XXX) and Jacobs (XYY) syndromes. Most were more common in SPARK than in MyCode. Jacobs syndrome, for example, appeared more than four times as often, which suggests that having XYY chromosomes is somehow causally related to having an autism diagnosis.
But Oetjens and his team didn’t consider the aneuploidies in isolation: Rather, they compared each against the baseline chromosomal makeups of XX and XY to determine the effect of adding either an extra X or an extra Y chromosome. When juxtaposed against XY, for example, Klinefelter syndrome—XXY—looks like an extra X chromosome; when compared with XX, it means having an extra Y.
There are complications to this approach, notes Donna Werling, assistant professor of genetics at the University of Wisconsin-Madison, who was not involved in the new work. Y chromosome genes aren’t the only difference between people with two X chromosomes and those with Klinefelter syndrome, for example: The latter are typically raised as male and have higher testosterone levels than most women (though lower levels than most men).
“Those extra Y effects in those comparisons are likely confounded by gonadal hormone exposures,” Werling says.
But the effects of an additional Y chromosome were easier to discern by comparing people with XYY and those with XY chromosomes, who have similar hormone levels. And, just as people with Klinefelter appear more likely to have autism than XX women, so too do people with Jacobs seem more likely to have autism than XY men.
This same analytical strategy revealed that having only a single X chromosome increases the chances of having autism, as does having an extra X chromosome—though the extra X appears to have a more modest effect than the extra Y. The findings appeared last month in Nature Communications.
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or researchers interested in sex differences, the extra Y effect is especially intriguing: If the Y chromosome does indeed contribute to the chances of having autism, perhaps those contributions can partially explain why autism is so much more prevalent in men than in women.“This study is very helpful in narrowing the search space for what some of the biological factors might be,” says Joseph Dougherty, professor of genetics and psychiatry at Washington University in St. Louis, who was not involved in the study. “There’s not that many genes on the Y chromosome.”
Werling, too, thinks that this study points toward a bigger role for sex chromosomes in autism likelihood than previously acknowledged. But she is not ready to conclude that the tangle of threads contributing to autism’s sex bias has been cut free. “I don’t think we can infer much about XX and XY individuals yet,” Werling says. “But what this study does is highlight a door for us to open.”
