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EXPERT REACTION: Genetic study finds possible links to male sexual orientation

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The first genome-wide screen looking for genetic factors in male sexual orientation found differences between gay and straight men linked to genes which have a potential role in sexual orientation, according to a US study. But don't go crying 'gay gene' just yet - the researchers say their results are at best speculative. The US researchers recruited around 1,000 homosexual men and 1,200 heterosexual men (most of European ancestry) identifying two particular genetic regions where differences were more common than average between the groups – one linked to development of a brain region which can differ with sexual orientation, and another linked to thyroid function.

Journal/conference: Scientific Reports

DOI: 10.1038/s41598-017-15736-4

Organisation/s: NorthShore University HealthSystem Research Institute

Media Release

From: Springer Nature

Looking for genetic links to male sexual orientation

A preliminary genome-wide association study (GWAS) of male sexual orientation is presented in Scientific Reports this week. Although the findings suggest genetic differences near genes that may have functions associated with sexual orientation, the authors note that potential connections are at best speculative.

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

Alan Sanders and colleagues conducted a GWAS of male sexual orientation involving 1,077 homosexual men and 1,231 heterosexual men, primarily of European ancestry. 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 genes for 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.

The authors note that the modest sample size in their study for a trait with complex genetics is a limitation, as is the focus on one ancestral group (European). They note that although the top two association peaks provide interesting and perhaps trait-relevant examples of their closest genes on chromosomes 13 and 14, the potential connections are hypothetical.

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Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Ilan Dar-Nimrod is a Member of the School of Psychology and the Charles Perkins Centre at the University of Sydney

Sanders and colleagues have conducted a genome wide association study in an attempt to further explore specific genes and changes in single letters of the genetic code, which differentiate gay and heterosexual men. Because such research transcends science, it has to take into account the wider effects it has on public discourse.
 
The focus on genetic underpinning for sexual orientation has a long history in science. 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 multitude of genes, and despite other studies failing to replicate the finding.
 
Research into the genetic underpinning of sexual orientation has been incorporated into social and cultural discourses. Advocates have made the argument that if there is a genetic underpinning for sexual orientation, then a person’s same-sex attraction will be viewed as unchangeable, inborn, and therefore beyond any reproach from viewing such attraction (and acting on it) as a choice. As a result, sexual orientation becomes imbued with essentialist thinking: there is an unchanging fundamental essence that all gay individuals share and heterosexual people do not.
 
However, this kind of argument has proven to be a double-edged sword. Some research has found that while learning about genetic attribution for homosexuality can make people more accepting of gay individuals, it can also lead people with anti-gay attitudes to polarise their views rather than mitigate them (1). The reason for that polarisation may arise from another aspect of essentialist thinking - discreteness - which draws clear divides between groups of people. In this instance it results in  a heterosexual person feeling a clear ‘us’ and ‘them’ that leads to distancing from ‘them’ (i.e. gay people). Such a feeling may fuel prejudice.
 
My own research found similar factors work among gay men themselves. While the naturalness of sexual orientation (e.g. genetic basis) is associated with decreased internalised homophobia, the feeling that the groups (i.e. heterosexual and gay people) are distinct is associated with increased internalised homophobia (2).
 
The movement toward seeing sexual choices among consensual adults as their own business, rather than a moral one, has been reflected in the discourse leading to the postal vote on gay marriage in Australia recently. As such it is hoped that misleading, sensationalising headlines such as ‘scientists discover gay genes’ are a thing of the past among informed journalists who are aware of how equating a person’s genes with their essence (3) can draw greater dividing lines between individuals based on their sexual orientation.
 
References:
 
(1) Boysen, G., & Vogel, D. (2007). Biased assimilation and attitude polarization in response to learning about biological explanations of homosexuality. Sex Roles, 56, 755-762.
(2) Morandini*, J., Blaszczynski, A., Ross M., Costa D. & Dar-Nimrod, I., (2015). Essentialist beliefs, sexual identity uncertainty, internalised homonegativity and psychological wellbeing in gay men. Journal of Counseling Psychology, 62, 413-424.
(3) Heine, S. J., Dar-Nimrod, I., Cheung*, B. Y. & Proulx, T. (2017).  Essentially biased: Why people are fatalistic about genes. Advances in Experimental Social Psychology, 55, 137-192. 

Last updated: 07 Dec 2017 3:25pm
Dr Nina McCarthy is a Research Fellow in the Centre for Genetic Origins of Health and Disease at the University of Western Australia

We know from family studies that genes may play a role in male sexual orientation; however which genes specifically may be involved has not been well studied. This paper reports the first published study which has examined genetic variants across the whole genome for association with homosexuality in European men. As this study was carried out in European men, we do not know whether the findings will apply to homosexuality in women, or even to homosexuality in non-European men.

This genome wide association study (GWAS) examined a relatively small number of men (approximately 2,300, including 1,100 homosexual men). Findings from small studies are less likely to be robust and less likely to be generalizable compared to large studies. In addition, the reported associations between variants in genes and homosexuality are not statistically significant, and the authors themselves say that they are ‘best characterized as speculative’.

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.
 
There has been one other (unpublished) GWAS of homosexuality in a much larger group of men by the US-based commercial company ’23andMe’. 23andMe reported an association between male homosexuality and a genetic variant in a gene called NKAIN3, which is involved in neuronal function. The same NKAIN3 variant shows weak evidence for association with homosexuality in this 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. 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.
 
GWAS may be able to point us in the direction of some genes which contribute incrementally to the biology of human sexuality. As for most complex human traits however, 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.
 
The justification for the research is unclear to me – the authors say that this study will ‘open a gateway to other studies focusing on genetic and environmental mechanisms of sexual orientation and development’. Although many would argue that knowledge should be acquired for knowledge’s sake, GWAS are usually carried out with an aim in mind – often to find out more about the underlying biology of an illness, so that we can better attempt to diagnose or fix that illness. As homosexuality is emphatically not an illness, the potential benefits of trying to better understand the underlying biology of homosexuality remain (to me) a little elusive.

Last updated: 07 Dec 2017 3:16pm
Dr Brendan Zietsch is an ARC Future Fellow in the School of Psychology at the University of Queensland

It is well established from twin and family studies that sexual orientation is partly heritable – that is, that whether someone is straight or bisexual or gay depends partly on their genetic makeup. However, twin and family studies cannot tell us which specific genes are involved.

Genome wide association studies (GWAS) aim to find the specific DNA variations that influence sexual orientation. Because there are so many bits of DNA (millions) 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 (2,038 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. No strong conclusions about the influence of specific genes on sexual orientation can be made at this point.

Last updated: 07 Dec 2017 3:13pm
Professor Vincent Harley is the Deputy Centre Head of the Center for Endocrinology and Metabolism at the Hudson Institute of Medical Research

This study is the first GWAS study of male sexual orientation. It analyses 1,077 homosexual men – a small study by GWAS standards. Linkage peaks were identified on chromosome 13 and 14, each with a neighbouring gene which show promise.

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. 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.

SLITRK6 is a neurodevelopmental gene expressed in the diencephalon, and a member of a gene family linked to behavioural phenotypes.

So the data is interesting and needs to be replicated in a larger cohort so that genome wide significance is reached within the study, rather than through combined analyses. It would also be great if the study was replicated in a different ethnic group.

Last updated: 07 Dec 2017 3:10pm

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