Male sexual orientation identified using epigenetic differences between twins

Epigenetic differences between male twins was used to identify sexual orientation with up to 67 percent accuracy, according to unpublished results presented at the American Society of Human Genetics 2015 annual meeting. Studying 37 pairs of twins in which one twin was homosexual and the other heterosexual, and 10 pairs of twins in which both were homosexual, researchers used a machine learning algorithm to isolate nine regions in the genome that differed in their DNA methylation – an epigenetic change which affects how genes are expressed – and could be used to predict participants’ sexual orientation.


Dr. Christopher Gregg, Assistant Professor of Neurobiology & Anatomy and Human Genetics, University of Utah (webpage):

Expertise: genome analysis and epigenetics with applications to neuroscience and behavior.

“Hormones have frequently been the focus of studies seeking to understand male and female sexual behaviors. Much less is known about epigenetic effects, which involve marks on the genome that change the expression of genes. Currently, DNA methylation is known to be required for normal brain development and function, and has been shown to change in response to stress, drug use and other factors. However, it is unclear whether DNA methylation changes at specific genes are sufficient to cause substantial behavioral effects.

“This new study investigates the possibility that specific epigenetic marks on the genome can be used as markers that indicate male heterosexual versus homosexual behavior. Note that this is not the same as finding that specific epigenetic marks are causing differences in sexual orientation. Thus, the authors’ claim that they have “new insights into the biological underpinnings of sexual orientation” appears to be overstated. The observed differences in epigenetic marks could arise as a consequence of the unknown biological factors that cause heterosexual versus homosexual behaviors, or due to lifestyle differences. Indeed, epigenetic marks differ between tissues and cells and, although it is not stated, the authors presumably analyzed blood samples from twins, rather than specific regions of the brain that control sexual behaviors and attraction. Therefore, the study does not provide evidence for “epigenetic influences on sexual orientation”, but it appears to have identified candidates for further investigation and an epigenetic signature that has some predictive utility in twins.

“The authors used a random forest classification approach, which is a powerful machine learning method that can produce very accurate predictions from complex datasets. When building a predictive model for epigenetic effects that are sensitive to environmental factors, it is especially important to control for other confounding factors, such as smoking, drug use, infections, body weight, environmental toxins and others. Therefore, the accuracy and interpretation of the authors’ results will, in part, depend on how effectively they controlled for confounding factors.

“Overall, the importance of these findings will hinge on how reproducible they are in future studies that include larger groups of heterosexual and homosexual individuals.”


Dr. Peng Jin, Professor of Human Genetics, Emory University (webpage):

Expertise: functions and mechanisms of epigenetics and noncoding RNAs in neurodevelopmental and neurodegenerative disorders.

“Sexual orientation is a complex behavior controlled by brain activity. The authors of this abstract utilized a very small number of samples and discovered certain epigenetic markers could be associated with sexual orientation. However, I am not sure whether “the predictive model” as claimed in the abstract is a correct term given the overall sample size. At best the authors could only claim the potential association, but not predicting power.

“It is unclear what tissues they used for epigenetic profiling. Blood DNA is likely the source, which could be the caveat of this study. It has been continuously debated whether the methylation status of blood DNA could be used as epigenetic biomarker for brain-related phenotypes. In addition, additional cytosine modifications have been discovered in recent years and the experimental system used in this study could not distinguish some of these modifications. The interpretation of their results could be limited.

“The observed epigenetic changes, particularly if from blood DNA, unlikely determine the complex behaviors, such as sexual orientation. These observations are potentially intriguing, however, interpreting these results certainly needs caution.”


Dr. Margaret M. McCarthy, Professor of Pharmacology, University of Maryland School of Medicine (webpage):

Expertise: mechanisms by which sexually dimorphic brain structures are formed, influence of steroid hormones on the developing brain

“The relative contributions of biology versus culture and experience in shaping sexual orientation in humans continues to be debated. The report by Ngun and colleagues provides important new information that is relevant to this question by revealing epigenetic changes in identical twins that correlate with their concordance on homosexuality. The authors surveyed the entire genome for epigenetic marks to the DNA that involve methylation of select nucleotides. Important roles for epigenetic changes in the brain have been implicated in neuropsychiatric disorders such as depression and suicide, drug addiction and in the coding of long term responses to fear, stress or starvation.

“In this study the authors prospectively explored whether sexual orientation is correlated with epigenetic changes. The stability and reliability of a frequency of 5-10% of male homosexuality in humans across all cultures, races and ethnic groups examined has bolstered the notion that there is a strong biological underpinning that involves a genetic component subject to selection. But there is also evidence of non-genetic components as evident in the lack of perfect concordance in identical twins. Monozygotic twins are a perfect example of the impact of epigenetics as their physical characteristics and personality traits diverge as they age, presumably in response to a life time of experience written in their epigenome.

“However epigenetic changes can also occur exceedingly early in life, even in utero in response to the maternal environment or in response to the fetus’s own hormones which vary both between and within the sexes. Developing male fetuses produce very high quantities of testosterone during the 2nd trimester and this directs psychosexual development along masculine lines, a component of which is preference for females as sexual partners. However, with some degree of regularity there are variables as yet unidentified that shift psychosexual development so that sexual partner preference is lessened or reversed.

“This study provides a major step forward in our understanding of how the brain can be affected by factors outside of the genome. It is also possible that the experience of being a homosexual or a heterosexual has itself impacted the epigenetic profile. But regardless of when, or even how, these epigenetic changes occur, their findings demonstrates a biological basis to partner preference.”


Declared interests (see GENeS register of interests policy):

No interests declared.



‘A novel predictive model of sexual orientation using epigenetic markers’ by T.C. Ngun et al., presented at the American Society of Human Genetics 2015 Annual Meeting on Thursday 8 October 2015.



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