Abstract
Male sexual orientation is influenced by environmental and complex genetic factors. Childhood gender nonconformity (CGN) is one of the strongest correlates of homosexuality with substantial familiality. We studied brothers in families with two or more homosexual brothers (409 concordant sibling pairs in 384 families, as well as their heterosexual brothers), who self-recalled their CGN. To map loci for CGN, we conducted a genome-wide linkage scan (GWLS) using SNP genotypes. The strongest linkage peaks, each with significant or suggestive two-point LOD scores and multipoint LOD score support, were on chromosomes 5q31 (maximum two-point LOD = 4.45), 6q12 (maximum two-point LOD = 3.64), 7q33 (maximum two-point LOD = 3.09), and 8q24 (maximum two-point LOD = 3.67), with the latter not overlapping with previously reported strongest linkage region for male sexual orientation on pericentromeric chromosome 8. Family-based association analyses were used to identify associated variants in the linkage regions, with a cluster of SNPs (minimum association p = 1.3 × 10–8) found at the 5q31 linkage peak. Genome-wide, clusters of multiple SNPs in the 10–6 to 10–8p-value range were found at chromosomes 5p13, 5q31, 7q32, 8p22, and 10q23, highlighting glutamate-related genes. This is the first reported GWLS and genome-wide association study on CGN. Further increasing genetic knowledge about CGN and its relationships to male sexual orientation should help advance our understanding of the biology of these associated traits.
Highlights
The normCGN score distributions are plotted by sexual orientation (Fig. 1), with a recapitulation of the patterns previously seen (Bailey & Zucker, 1995), namely that scores were more variable for homosexual men (M = 1.41, variance = 0.046) and clustered more tightly in the gender conforming region of the distribution for heterosexual men (M = 1.02, variance = 0.017)
Our multipoint nonparametric genome-wide linkage scan (GWLS) results (Fig. 2) show the four strongest peaks located on chromosomes 5 (136 ~ 152 cM, based on multipoint drop-1 LOD support interval), 6 (79 ~ 86 cM),7 (139 ~ 158 cM), and 8 (127 ~ 138 cM); three of these peaks contain SNPs with genome-wide significant two-point LOD scores, with respective two-point LOD maxima being 4.45, 3.64, and 3.67. We note that these locations do not overlap with previously reported linkage peaks for male sexual orientation, such as at pericentromeric chromosome 8 (Sanders et al, 2015)
The top regions (Supplementary Table 1). In this first GWLS on childhood gender nonconformity (CGN) in males, we found genome-wide significant linkage with multipoint support for several linkage regions, most notably at chromosomes 5q31 and 8q24 (Fig. 2, Supplementary Table 1)
Summary
Male sexual orientation is moderately heritable (30 ~ 40% heritability) and appears multifactorial, with evidence of multiple genetic and environmental contributions via family, twin, and segregation analyses (Alanko et al, 2010; Bailey & Bell, Evanston, IL, USA1 3 Vol.:(0123456789)Archives of Sexual Behavior1993; Bailey & Benishay, 1993; Bailey & Pillard, 1991; Bailey et al, 1993, 1999, 2000; Buhrich et al, 1991; Hamer et al, 1993; Heston & Shields, 1968; Kallmann, 1952; Kendler et al, 2000; King & McDonald, 1992; Kirk et al, 2000; Langström et al, 2010; Pattatucci & Hamer, 1995; Pillard & Weinrich, 1986; Santtila et al, 2008; Schwartz et al, 2010; Whitam et al, 1993). A second approach has examined the correspondence between homosexual men’s recalled childhood gender nonconformity and their mothers’ memories of their sons, finding a strong association, r = 0.69 (Bailey et al, 1995). In twin studies, CGN shows moderate to high heritability in males: 37% (Knafo et al, 2005), 70% (van Beijsterveldt et al, 2006), 29% (Alanko et al, 2010), and 50% (Bailey et al, 2000). Despite these findings, there have not yet been gene mapping efforts for CGN. We report the first GWLS and GWAS on CGN in males
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