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^–8 p-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.

男性性取向受环境和复杂遗传因素的影响。童年性别不符合 (CGN) 是同性恋与大量家庭最密切相关的因素之一。我们研究了有两个或更多同性恋兄弟的家庭中的兄弟（384 个家庭中的 409 对兄弟姐妹，以及他们的异性恋兄弟），他们自我回忆了自己的 CGN。为了绘制 CGN 的基因座，我们使用 SNP 基因型进行了全基因组连锁扫描 (GWLS)。最强的连锁峰，每个都有显着或暗示性的两点 LOD 得分和多点 LOD 得分支持，位于染色体 5q31（最大两点 LOD = 4.45）、6q12（最大两点 LOD = 3.64）、7q33（最大两个点 LOD = 3.09）和 8q24（最大两点 LOD = 3.67），p  = 1.3 × 10 ^–8 ) 在 5q31 连锁峰发现。在染色体 5p13、5q31、7q32、8p22 和 10q23 上发现了全基因组范围内 10-6 到 10-8 p 值范围内的多个 SNP 簇，突出^了谷氨酸相关基因。这是首次报道的关于 CGN 的 GWLS 和全基因组关联研究。进一步增加关于 CGN 及其与男性性取向关系的遗传知识应该有助于促进我们对这些相关特征的生物学的理解。