Why Autism Is More Common in Males: Testosterone Affects Gene

A new study offers some clues into the mystery of why autism is four times more common in males than in females.

The results show that testosterone and estrogen have opposite effects on a gene nicknamed RORA. In neurons, testosterone lowers the ability of cells to express, or turn on, the RORA gene, while estrogen raises it.

"Autism has a huge sex bias, and it's been proposed that higher levels of fetal testosterone may put a fetus at risk," said study researcher Valerie Hu, professor of biochemistry and molecular biology at George Washington University in Washington, D.C. "We've provided an explanation of how this works."

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Normally, RORA's job in cells is to turn on several other genes, Hu said. When a cell has high levels of testosterone, RORA levels run low, which affects every gene that RORA is supposed to turn on. The researchers based their findings on tests of neurons growing in lab dishes.

The research does not show that low levels of RORA cause autism, only that they are associated with the condition, Hu said. But other research has suggested that a RORA deficiency could explain many of the effects seen in autism.

For example, the gene has been shown to protect neurons against the effects of stress and inflammation — both of which are elevated in autism, she said.

And research has shown that the brain tissues of people with autism contain lower levels of RORA than those of people without the condition, Hu told MyHealthNewsDaily.

RORA is also believed to be help maintain the body's daily circadian rhythm, and people with autism frequently experience sleep disturbances, she said.

Also, mice that have been genetically engineered to lack the gene engage in a number of behaviors suggestive of autism, she said.

Unlike testosterone, estrogen raises RORA levels in cells, Hu said.

This means that females may have be protected against autism — even if RORA levels were otherwise low, estrogen can "pick up some of the slack," Hu said.

"We're not saying that RORA is the only gene" involved in autism, "but it's likely one of the critical ones," Hu said.

The findings fit with ideas about autism proposed by researchers led by Simon Baron-Cohen, the director of the Autism Research Centre at the University of Cambridge in England, Hu said. Baron-Cohen proposed that high levels of testosterone in a fetus were correlated with autistic traits, and his work has demonstrated that high testosterone levels in the amniotic fluid are associated with the condition.

Hu said her new study adds to that work by proposing a mechanism linking testosterone with autistic behaviors.

However, other researchers have explained autism's higher prevalence in males differently, Hu said. They suggest that genes on the X chromosome play a role in autism. Because females have two X chromosomes, and males have only one (combined with a Y chromosome), females have a "backup" copy of any gene that is mutated.

Although this theory is plausible, to date, no genes on the X chromosome have unequivocally been associated with autism, Hu said.

The new findings are published in the February issue of the journal Public Library of Science ONE.

Follow MyHealthNewsDaily Managing Editor Karen Rowan @karenjrowan