A genetic analysis of gay siblings supports the idea that genes on the X chromosome contribute to male homosexuality.

A genetic analysis of gay siblings supports the idea that genes on the X chromosome contribute to male homosexuality.

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Study of gay brothers may confirm X chromosome link to homosexuality

Dean Hamer finally feels vindicated. More than 20 years ago, in a study that triggered both scientific and cultural controversy, the molecular biologist offered the first direct evidence of a “gay gene,” by identifying a stretch on the X chromosome likely associated with homosexuality. But several subsequent studies called his finding into question. Now the largest independent replication effort so far, looking at 409 pairs of gay brothers, fingers the same region on the X. “When you first find something out of the entire genome, you’re always wondering if it was just by chance,” says Hamer, who asserts that new research “clarifies the matter absolutely.”

But not everyone finds the results convincing. And the kind of DNA analysis used, known as a genetic linkage study, has largely been superseded by other techniques. Due to the limitations of this approach, the new work also fails to provide what behavioral geneticists really crave: specific genes that might underlie homosexuality.

Few scientists have ventured into this line of research. When the genetics of being gay comes up at scientific meetings, “sometimes even behavioral geneticists kind of wrinkle up their noses,” says Kenneth Kendler, a psychiatric geneticist at Virginia Commonwealth University in Richmond. That’s partially because the science itself is so complex. Studies comparing identical and fraternal twins suggest there is some heritable component to homosexuality, but no one believes that a single gene or genes can make a person gay. Any genetic predispositions probably interact with environmental factors that influence development of a sexual orientation.

Several genomic studies have suggested regions that might influence sexual orientation, but they have relied on small numbers of participants and have been challenged repeatedly. In 1993, Hamer, then at the U.S. National Institutes of Health (NIH) in Bethesda, Maryland, published the first of these studies, suggesting that a specific stretch of the X chromosome called Xq28 holds a gene or genes that predispose a man to being gay.

The finding made some evolutionary sense. An X-linked gene for homosexuality has long been proposed as a way to explain how the trait persists in the population even though gay men tend to have fewer offspring: The gene could increase fertility in females, who would have two “chances” to inherit it.

Many researchers were skeptical that an analysis of only 38 pairs of gay brothers was reliable, and several other groups failed to replicate the results. “In my circles, it was seen as ‘Oh, another false-positive finding,’ ” Kendler says. “Findings in this general area of human behavioral genetics were at that time really plagued by concerns about replicability.”

The paper also ignited social debate: Some speculated that a genetic test for homosexuality would lead to more discrimination, while others attacked the premise that being gay has a biological basis. “For a long while, if you Googled my name, you would find right-wing religious webpages saying that I was a liar,” says Hamer, who formally retired from NIH in 2011.

J. Michael Bailey, a psychologist at Northwestern University in Evanston, Illinois, wanted to put questions about Xq28 to rest. “I thought that Dean did a fine but small study,” he says. “If I had to bet, I would have bet against our being able to replicate it.” In 2004, he began to recruit families with at least two gay male siblings for a genetic linkage analysis, which searches for regions of DNA consistently shared between people with a common trait.

When Bailey and his colleagues analyzed the DNA of the 409 pairs of brothers they had recruited, they were surprised to see linkages on both Xq28 and a region of chromosome 8, which Hamer had also previously suggested held genes related to sexuality.

The work, published online today in Psychological Medicine, took longer to come to light than many expected. After more than 7 years chipping away at the analysis between other projects, Bailey and psychiatrist Alan Sanders of NorthShore University HealthSystem Research Institute in Evanston, who led the investigation, began to discuss their findings at meetings. But it would be nearly 2 more years to publication, and Sanders acknowledges that at least one journal rejected the work.

In the meantime, the genetic linkage technique has largely been replaced with genome-wide association (GWA) studies. A linkage study identifies only broad regions containing dozens or even hundreds of genes, whereas GWA studies often allow the association of a specific gene with a certain trait in the population. That approach would be preferable, but a linkage study was the only way to directly replicate Hamer’s work, Sanders says.

Kendler, who is an editor at Psychological Medicine, says it was somewhat surprising to get the submission from Sanders and Bailey’s team using the older technique. “Seeing linkage studies in this world of GWAs is rare,” he says, but he maintains that the study “really moves the field along.”

Neil Risch, a geneticist at the University of California, San Francisco, disagrees. The paper does little to clear up question about Xq28, he says. Risch collaborated on a 1999 study that found no linkage at that region and says that more recent evidence casts further doubt. He also says the two linkages reported in the new work are not statistically significant.

Sanders admits that although the strongest linkage he identified on chromosome 8, using an isolated genetic marker, clears the threshold for significance, the Xq28 linkage does not. But he says both cases are bolstered by (also less-than-significant) data from neighboring markers, which appear to be shared at higher rates between pairs of brothers. “The convergence of the evidence pointed towards” Xq28 and chromosome 8, he asserts.

Bailey and Sanders may soon have more data to back their claim—or refute it. They’re now working on a GWA study, which includes genetic data from the just-published work plus DNA samples from more than 1000 additional gay men. Based on the results published today, “it looks promising for there being genes in both of these regions,” Bailey says, “but until somebody finds a gene, we don’t know.”

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