There is no “gay gene” — as a study looks for genetic basis of sexuality

The largest study yet on the genetic basis of sexuality [see article plus two editorials, attached] has revealed five nucleotides within the human genome that are “linked to same-sex sexual behavior”; however, none of the markers was concluded to be sufficiently reliable to predict someone’s sexuality. These findings are based on the genomes of almost 500,000 people. These conclusions confirm results of earlier smaller studies: although “sexual preference” undoubtedly is a multifactorial trait and might have a genetic component — no single “large-effect” gene, or several genes, is/are detectable. Authors [see attached] used their analysis to estimate that “as much as 25% of sexual behavior might be explainable by genetics” (i.e. ‘nature’), with “the remainder influenced by environmental factors including cultural effects” (i.e. ‘nurture’); this is only the authors’ politically correct conclusion.

There are many caveats to this study. “The results might not be representative of the overall population” — a limitation that the study authors acknowledge. “Most of the genomes come from the UK Biobank research program and the consumer-genetics company 23andMe (based in Mountain View, California). “Those people who share their genetic and health information with those databases are mostly of European ancestry and tend to be older.” UK Biobank participants were “between 40 and 70 years old when their data were collected,” and “the median age for people in 23andMe’s database is 51.” Across various human societies and in both sexes, at least 2% of individuals report “engaging in sex with same-sex partners — either exclusively, or in addition to sex with opposite-sex partners.” Twin-pair and family studies have shown that same-sex sexual behavior is partly genetically influenced, but every search for “specific genes involved” has been statistically underpowered to detect effect-sizes that are realistic for complex traits.

Authors conclude that “same-sex sexual behavior is influenced by — not one or a few genes — but many genes.” I am not so sure of this study. Analysis of different aspects of sexual preference underscore its complexity and call into question the validity of bimodal continuum measures such as the Kinsey scale. “Nevertheless, many uncertainties remain to be explored,” say the authors, “including how sociocultural influences on sexual preference might interact with genetic influences.” Agreed.

In the publication, I searched for those five “breakthrough single-nucleotide variants (SNVs)” and found that:

rs11114975 is a PPF1A2 pseudogene intron variant (antisense RNA to PPF1A-binding protein).

rs10261857 is an unidentified gene, but “is statistically associated with oligoarticular RF-negative polyarticular Juvenile Idiopathic Arthritis (JIA), with a false discovey rate (FDR) of <0.05)” — from a PhD thesis from the University of Cincinnati College of Medicine(!!). rs28371400 is an unidentified RNA non-coding gene, LOC145783. rs34730029 is within the MPEG1 (macrophage-expressed 1) gene, but is an intronic SNV. rs13135637 is an SNV that I could not find — anywhere in the publication or in the Authors’ Supplementary Data online. I asked for, and received, excellent reviews of this paper by TWO “anonymous population geneticists” — [1] I don’t doubt that one or more of these might be “real” associations. But – it is the usual GWAS thing, absolutely no way to track down the trait to any credible candidate gene(s). So, what does it really mean? In my humble opinion, as a Reviewer, I would have rejected this manuscript. My impression is that Science simply wanted to publish a paper on this (controversial) topic and get a big boost in their readership, a splash in publicity. Although the “generally accepted 5.0e–08 level of genome-wide significance” is reached, these five SNVs remain complete mysteries. Perhaps in 10-20 years, GWAS science will be able to explain such spurious SNVs associated with such a highly complex trait? [2] In the news I have seen and heard about this paper everywhere. I agree with you that Science simply wanted to get more public attention by publishing research on this “hot topic.” I initially did not read this paper – because one can “always find significant genetic associations with almost everything.” The authors this time were clever enough to have selected a phenotypic trait that was likely to be accepted for publication by the prestigious Science magazine! One of the senior authors, Dr. Benjamin M. Neale, is a very good statistical geneticist – he has analyzed hundreds to thousands of phenotypic traits in UK Biobank, but only this one has been accepted for publication in Science! The GWAS findings (the five SNVs) of this paper are statistically not very robust. Although they reached genome-wide significance (5.0e–08), more stringent significance levels have recently been proposed for GWAS, because with large samples we can now impute more low-frequency SNVs. Furthermore, only three of these SNVs were (nominally) replicated. I checked the dbSNP database, and all three of these variants showed significant allele frequency differences between populations; in my thinking, this fact makes them more liable to be population stratification artifacts (population stratification is the presence of a systematic difference in allele frequencies between subpopulations, within the study population, likely caused by different ancestry and/or the way in which individuals were chosen for the association study). Nowhere in the paper did the authors specifically mention how they controlled for population substructure. They only mentioned “the studied participants are of European ancestry” – as a limitation in the ‘Discussion’ segment of the paper. In addition to these “shabby” GWAS data, there are actually several interesting observations reported in this paper which might encourage people to think a little more deeply about “same-sex sexual behavior” as a biological trait: Figure 1A. The percentage of same-sex sexual behavior was found to increase almost 4-fold in 30 years (!) – this is definitely a sign of a social/cultural trait instead of a biological trait; Figure 1B. The “reproductive disadvantage” of “same-sex sexual behavior” was very high – if this were a biological and evolutionary trait with any substantial genetic contribution, this trait would have decreased in rate, instead of this 4-fold increase in rate over the past 30 years; Figure 4. The genetic correlations with risky behavior (e.g. cannabis use), mental health, and number of sex partners – as well as the recent staggering 4-fold increase in 30 years – makes me tend to believe that “same-sex sexual behavior” is not a “primary biological trait” but rather a “secondary response” (i.e. a behavioral pattern under a specific cultural environment, e.g. leisure and affluence). My conclusion is somewhat different from the “politically correct” statement mentioned in the Wall Street Journal article: “This new study provides even more evidence that being gay or lesbian is a natural part of human life, a conclusion that has been drawn by researchers and scientists time and again.” Lastly, I believe that “being gay or lesbian or whatever” need not be, and should not be, vindicated by biology. Otherwise, we can simply do whatever monkeys like to do. I am not against “being gay or lesbian” – I respect them and I have many homosexual friends and they should feel happy to be what they are. We do not need to “justify” “same-sex sexual behavior,” by saying “it is a natural thing, based on genetics.” DwN · · Science 30 Aug 2019; 365: 882 eaat7693(2019); editorial pp. 869-870; editorial in Nature 5 Sept 2019; 573: pp 14-15

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