The once-prevailing concept of a “gay gene” dictating sexual orientation has been put to rest in a powerhouse study published today in Science. The work brilliantly illustrates the very nature of science: evolving with the input of new data, especially the large-scale contributions of bioinformatics and crowd-sourcing.

“We formed a large international consortium and collected data for more than 500,000 people, comparing DNA and self-reported sexual behavior. This is approximately 100 times bigger than any previous study on this topic,” said lead author Andrea Ganna, of the Institute of Molecular Medicine in Finland and an instructor at Massachusetts General Hospital and Harvard Medical School, opening a news conference earlier this week.

Human Sexuality is Nuanced and Complex

The investigation estimates a genetic contribution to same-sex sexual behavior as under 1 percent, thanks to analysis of a trove of data from the UK Biobank and the consumer genetic testing company 23andme. That’s good news.

I hope that the demonstration of a diminished role for genetics will counter the idea that having sex with a person of the same sex is something biologically broken that needs to be fixed. Yet I wonder how the findings might be twisted or otherwise misinterpreted. “Using these results for prediction, intervention, or a supposed ‘cure’ is wholly and unreservedly impossible,” points out Melinda Mills, a sociologist from the University of Oxford in an accompanying Perspective.

Sums up team member Ben Neale, from the Broad Institute and the Analytic and Translational Genetics Unit at Massachusetts General Hospital:

“This study provides the clearest glimpse yet into the genetic underpinnings of same-sex sexual behavior. It highlights the complexity of the genetics, but genetics is not the whole story. It also underscores an important role for the environment in shaping human sexual behavior and perhaps, most importantly, that there is no single gay gene, but rather the contribution of many small genetic effects scattered across the genome.”

Thousands of genes each exert tiny influences.

The international research team developed a website (password gwas) about the study that uses plain language, after consulting LGBTQIA+ outreach and advocacy groups.

That input was critical, considering the murky history of the search for a “gay gene.”

In 1993 Dean Hamer, then at the NIH, famously published a paper in Science hypothesizing that a gene or genes predisposing a man to same-sex behavior resides near the tip of the long arm of the X chromosome, a region dubbed Xq28. The idea stemmed from the observation that gay men tended to have more gay relatives on their mothers’ side than on their fathers’, suggesting a role for the X, which males get from their mothers. The evidence: 33 of 40 pairs of gay brothers share that region.

Through the lens of today’s big data, it’s amazing that such a limited study could have had such traction, but it inspired headlines back then. Here’s how John Crewdson, writing in the Chicago Tribune in 1995, attempted to temper the hype: “Dean Hamer doesn’t claim to have found the gene, or even the set of genes, that contributes to a propensity for homosexuality. What Hamer reported in a July 1993 article in Science magazine is statistical evidence that such genes exist.”

It isn’t that simple.

Fah Sathirapongsasuti, senior scientist for computational biology at 23andMe and a team member, remembers reading the Hamer paper as a teen trying to understand his sexuality:

“I looked at the Internet for “gay gene” and came across Xq28, and readily blamed it on my mom because she gave me my X chromosome. Well, luckily for her, these papers have basically disproved that theory and now the blame is shared equally between my mom and my dad.”

The turnaround celebrates how science works. We disprove hypotheses in science, we don’t ever “prove” anything – the advertising industry invented “scientific proof.” Conclusions can change as new data accumulate – that’s especially likely when technology accelerates, such as replacing 40 data points with more than half a million, as is the case in the new work.

Comparing Points Along Genomes

The new study is a “GWAS,” one of the worst abbreviations in genetics, which has quite a few. GWAS means “genome-wide association study.” It compares a large set (at least hundred of thousands) of single-base sites (SNPs) in genomes that vary – that is, can be A, C, T, or G – among individuals.

If people with a specific trait or illness share sweeping GWAS patterns, then a genetic component is inferred. It’s a little like comparing many points of interest encountered on a cross-country drive and concluding, if two cars share the same stops, that they’ve followed the same route.

With high numbers of SNPs and people, powerful associations can emerge. Still, validation in other populations, plus deep knowledge of biochemistry and cell biology, are required to elevate an association or even a correlation (a directional association) to causality.

A GWAS is sometimes simplified to a “polygenic risk score,” but either way the measurement is a subtle look at genetic variation. It’s not an analysis of a single mutant gene, like the one behind sickle cell disease.

The UK Biobank contributed responses from 408,995 people and 23andMe contributed 68,527. But it’s the nuanced nature of how the company amassed its data that lies behind the revelation that is really an affirmation of the many ways that people express their sexuality. 23andMe allowed for fluidity of sexual preference.

Kudos for 23andMe: Beyond Binary

Participating in 23andMe research is fun. Their emails are piling up in my in box right now:

“Just a friendly reminder that your:

Matching speed cognitive game

Healthy aging survey

Spot-the-difference cognitive game

Hearing-in-a-crowd test

Recent dietary habits survey

is available in your 23andMe account.”

The “sexual orientation” survey is popular, Neale said.

Like many other geneticists, I didn’t at first support what was initially called direct-to-consumer genetic testing, but I changed my mind after the company identified two genes behind Parkinson’s disease in record time, thanks to customers sharing data.

For the new study, 23andMe asked:

“With whom have you had sex?” and for people reporting ever having had sex with the same sex, followed up with a fleshing out of the answer: “other sex mostly,” “other sex slightly,” “equal,” “same sex slightly,” “same sex mostly,” or “same sex only.” If the UK Biobank approach is like a true-false question on an exam, then the 23andMe approach is like a detailed multiple choice question. Nuance.

After the math, for a GWAS is a computational tool, the researchers concluded that whether a person has ever or never had sex with the same sex is distinct, in terms of the minuscule genetic influence, from the proportion of same-sex partners. Therefore, the two questions “capture aspects of sexuality that are distinct on the genetic level, which in turn suggests that there is no single continuum from opposite-sex to same-sex sexual behavior,” the researchers write.

This complexity is in stark contrast to the Kinsey scale, commonly used to measure sexual orientation, which assumes that greater attraction to the same sex diminishes attraction to the opposite sex. “The Kinsey scale is an oversimplification of the diversity of sexual behavior in humans,” said Neale.

The Data

Initially the GWAS showed that the genetic contribution to variation in same-sex sexual behavior is 8 to 25%. But when the researchers used a technique, SNP-heritability, that assesses more SNPs and includes very rare ones, genes explained less than 1% of the variation. “The effects are so small that this genetic score cannot in any way be used to predict same-sex sexual behavior of an individual,” Mills writes.

That’s critical. We can’t look at a person’s DNA sequence and predict sexual behavior. At all. Ever.

Five SNPs stood out as being “significantly associated with same-sex behavior” compared to the thousands of others, two in males only and one in females only. Finding these five, though, is like looking at a very tiny pebble in a handful of sand of many particle sizes. Overall females and males share only 63% of the gene regions associated with sexual orientation, which is a lot less alike than for many other traits. Not terribly surprising.

One of the SNPs is near genes that affect the sense of smell (for males). Two others are near genes that regulate sex hormones, in females and males. And none were on the X chromosome, for so many years thought to house the debunked gay gene.

The researchers identified several characteristics exhibiting a “genetic correlation” to same-sex orientation:

• Personality traits of loneliness and openness to experiences
• A fondness for weed and cigarettes
• Depression (females more than males)
• Schizophrenia (females slightly more than males)

But no physical traits went along with same-sex experience, perhaps countering some stereotypes.

The researchers point out that the apparent increase in mental illness can just as easily reflect the effects of prejudice as it does DNA, especially among older participants from the UK who recall the criminalization of same-sex behavior. Cryptanalyst Alan Turing is a telling case. He was convicted of “gross indecency” in 1952 and given a choice of prison or taking estrogen. He chose the hormone and killed himself two years later.

The 1% genetic input leaves a lot of room for other influences. “Sexuality is dynamic, with the ability to express and realize sexual preferences, and is thus also shaped and regulated by cultural, political, social, legal, and religious structures,” Mills writes.

In other words, the new data seem to echo what people already know from just being people. “The diversity that we see in the genetic analysis reinforces the message that the expanding acronyms in the LGBTQIA+ community is real,” said Neale.

A One-of-a-Kind Report

The Eunice Kennedy Shriver National Institute of Child Health and Human Development funded the research to probe the genetic influence on sexual orientation. The project began in 2012.

The Science paper is remarkable in the interactions with the community of people the research addresses. A special box explains word choices. For example, instead of “homosexual,” the term used is “nonheterosexual,” meant only to distinguish clearly, not to judge. Female and male are the biological terms used; not woman and man.

The researchers mention the limitations of their study: reliance on older, Euro-centric populations, as well as the bias in the 23andMe data. In various societies, the percent of people having sex with the same sex ranges from 2 to 10%, yet 19% of the 23andMe respondents report ever having sex with the same sex.

Because the team took such extraordinary measures to relay their important message clearly, I’ll end with their interpretation:

“Our results overwhelmingly point toward the richness and diversity of human sexuality. … not toward a role for discrimination on the basis of sexual identity or attraction, nor do our results make any conclusive statements about the degree to which ‘nature’ and ‘nurture’ influence sexual preference.”