Epigenome-wide association study of sexual orientation in monozygotic twins. T. C. Ngun1, W. Guo2, N. M. Ghahramani3, K. Purkayastha1, F. J. Sanchez4, S. Bocklandt1, M. Zhang2, 5, M. Pellegrini6, E. Vilain1 1) Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USALos Angeles, CA; 2) Bioinformatics Division and Center for Synthetic & Systems Biology, TNLIST, Tsinghua University, Beijing 100084, China; 3) Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 4) Department of Counseling Psychology, The University of Wisconsin-Madison, WI, USA; 5) Department of Molecular and Cell Biology, Center for Systems Biology, The University of Texas at Dallas, Richardson, TX 75080, USA; 6) Department of Molecular, Cellular, and Developmental Biology, UCLA, Los Angeles, CA, USA.

   Sexual orientation is one of the most pronounced sex differences in the animal kingdom. Although upwards of 95% of the general population is heterosexual, a small but significant proportion of individuals (3-5%) is homosexual. Previous work has consistently shown that sexual orientation has a strong genetic component. Male sexual orientation has been linked to several genomic loci including Xq28, 8p12, and 10q26, which is an imprinted region. As with other complex traits, environmental factors also play an important role. For instance, monozygotic twins show substantial levels of discordance for this trait. Additionally, each biological older brother a man has increases the probability of him being gay by 33%. Taken together, the evidence strongly suggests a role of epigenetic mechanisms in the regulation of sexual orientation. We aim to elucidate the molecular mechanisms underlying sexual orientation by investigating DNA methylation patterns on a genome-wide basis in 34 monozygotic male twin pairs that are discordant for sexual orientation using reduced representation bisulfite sequencing (RRBS). As a control population, we also performed RRBS on 10 monozygotic twin pairs concordant for homosexuality. Subjects were classified as homosexual or heterosexual based on their sexual feelings (as measured by the Kinsey scale). We first consolidated nearby CpG sites into short regions (100-500 bp) to increase the signal to noise ratio in our data. A linear mixed modeling approach was used to identify regions that were significantly associated with sexual orientation (sexual orientation DMRs). At a false discovery rate of 10%, we identified 136 sexual orientation DMRs. One of these regions was in 10q26 but there were no other overlaps between our data and previous linkage findings. This discrepancy was not surprising as prior studies primarily used families with evidence of maternal loading, which was not a criteria for inclusion in our study. Several genes associated with sexual orientation DMRs were involved in the androgen signaling pathway: (1) AR, which encodes the androgen receptor; (2) ZDHHC7, which regulates the localization of sex steroid receptors; and (3) SULT1A3, which is part of the alternative androgen synthesis pathway. Our findings demonstrate that numerous epigenetic changes are associated with sexual orientation in humans and that our approach has the potential to identify novel genes that influence this trait.

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