Scientists find possible genetic links to male sexual orientation

While Australia’s LGBTIQ+ community celebrates the legalisation of same-sex marriage, US researchers are continuing the search for the elusive ‘gay gene’.

Male sexual orientation is multifactorial, with evidence of multiple genetic and environmental contributions. However, genetic association studies for male sexual orientation have been sparse, with results mixed at best.

“The focus on genetic underpinning for sexual orientation has a long history in science,” said Dr Ilan Dar-Nimrod from the University of Sydney. “With advancements in molecular biology, it has been a constant area of investigation since Hamer et al (1993) published findings that implicated a region on the X chromosome — Xq28. At the time, Xq28 was dubbed as the ‘gay gene’ in popular media, despite being a region that contains a multitude of genes, and despite other studies failing to replicate the finding.”

Now, a research team led by NorthShore University HealthSystem’s Research Institute has conducted its own preliminary genome-wide association study (GWAS) of male sexual orientation. The study involved 1077 homosexual men and 1231 heterosexual men, primarily of European ancestry. Published in Scientific Reports, it is said to be the study of its kind in a peer-reviewed scientific journal.

Participants were rated for sexual orientation based on their self-reported sexual identity and sexual feelings. They were then asked to provide DNA by blood or saliva samples that were then genotyped and analysed. The authors detected several regions with multiple single nucleotide polymorphisms (single-letter changes in the DNA), the most prominent of which were located on chromosomes 13 and 14 near genes that have functions plausibly relevant to the development of sexual orientation.

The strongest associated region on chromosome 13 was located between the genes SLITRK6 and SLITRK5. SLITRK6 is a neurodevelopmental gene mostly expressed in a region of the brain called the diencephalon, which contains a region previously reported as differing in size in men depending on their sexual orientation. On chromosome 14, the TSHR (thyroid stimulating hormone receptor) gene spans the region around the most significant single nucleotide polymorphism. Genetic variants in TSHR may conceivably help explain past findings linking atypical thyroid function and male homosexuality.

“TSHR, encoding the receptor for thyroid stimulating hormone is intriguing because Danish same-sex married men have higher rates of atypical thyroid function, called Graves’ disease,” noted Professor Vincent Harley from the Hudson Institute of Medical Research, who was not involved in the research. “The authors add further plausibility to TSHR being a good candidate, citing skewed X inactivation observed by separate groups studying Graves’ disease and homosexual men.”

The authors acknowledged that the modest sample size in their study for a trait with complex genetics was a limitation, as was the focus on one ancestral group (European) and on one sex (males). They also emphasised that although the top two association regions provide interesting and perhaps trait-relevant examples with their closest genes, the potential connections remain speculative.

Commenting on the results, Dr Brendan Zietsch, an ARC Future Fellow at The University of Queensland, was particularly critical of the sample size. He stated, “Because there are so many bits of DNA that vary among people, finding the relevant DNA bits is like finding a needle in a haystack. Therefore, very large samples of participants are required.

“This particular study is very small (2038 participants) by the standards of modern GWAS (often more than 100,000 participants). Not surprisingly, it did not detect any associations that reach a conventional statistical standard of evidence that means we can be confident in the finding.”

Dr Nina McCarthy, a research fellow at The University of Western Australia (UWA), was similarly sceptical. She pointed out a number of issues with the study, claiming, “Findings from small studies are less likely to be robust and less likely to be generalisable compared to large studies. In addition, the reported associations between variants in genes and homosexuality are not statistically significant.

“When considering the results of GWAS, it’s really important to appreciate that association does not imply causation. Although there are no effect sizes reported in the paper, the increased likelihood of being homosexual that is associated with carrying one of these genetic variants will be tiny. All that is required to see a genetic association in this study is for slightly more homosexual men to carry the genetic variant than heterosexual men, and many times this will simply be due to chance.”

Dr McCarthy did, however, acknowledge a similarity with an unpublished GWAS of homosexuality in a larger group by the US-based company 23andMe, which reported an association between male homosexuality and a genetic variant in a gene called NKAIN3, involved in neuronal function. The same NKAIN3 variant shows weak evidence for association with homosexuality in the current study.

“The fact that the same gene is (weakly) associated with male homosexuality in two independent studies means that this may be a true association, although it is not definitive proof,” Dr McCarthy said. “The authors also comment on a weak association in this study between the gene TSHR, which is involved in thyroid stimulation, and male homosexuality, although I believe this is premature as this group is the only one to have shown this association.”

Ultimately, Dr McCarthy believes that “no single gene is likely to have a large influence on human sexuality”.

“Rather, a very complex and highly dimensional array of biological and environmental factors are likely to determine sexuality in a different way for each individual. Hence the findings of genetic studies of homosexuality are very unlikely to ever lead to a genetic ‘test’ for homosexuality.”

Corresponding author and psychiatrist Alan Sanders is more optimistic about the findings, claiming, “Because sexuality is an essential part of human life — for individuals and society — it is important to understand the development and expression of human sexual orientation.

“The goal of this study was to search for genetic underpinnings of male sexual orientation, and thus ultimately increase our knowledge of biological mechanisms underlying sexual orientation. What we have accomplished is a first step for GWAS on the trait, and we hope that subsequent larger studies will further illuminate its genetic contributions.”

Image credit: ©stock.adobe.com/au/Jezper