Genome-Wide Linkage and Association Study of Childhood Gender Nonconformity in Males

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.

Probing the genomic landscape of human sexuality: a critical systematic review of the literature

“…Gender nonconformity, or more contemporarily gender variance, has been found to be one of the strongest correlates of homosexuality, displaying a high amount of familiarity. We were able to find only one linkage/GWL/GWAS investigation, carried out by Sanders et al ( Sanders AR. et al, 2021 ) in 2021.…”

Queering genomics: How cisnormativity undermines genomic science

“…Genomic research, which relies heavily on standardized definitions of genotypes and phenotypes to identify correlations between them, is especially hamstrung by the shortcomings of imprecise frameworks for the collection of data on sex and gender. Examples include studies that employ vague terms to describe constructs with contested and dubious validity, such as “childhood gender nonconformity,” 52 studies that deliberately exclude participants whose sex characteristics and gender do not align, 53 and studies that conflate sex and gender as predictors of disease susceptibility or to explain differences in body composition and disease risk. 54 , 55 Relying on misspecified and insufficiently nuanced sex and gender categories to understand human variation is an epistemically flawed practice that results in the erasure, stigmatization, and mistreatment of people and the generation of unsound science.…”

Polygenic scores clarify the relationship between mental health and gender diversity

“…One method to estimate pleiotropy is to use polygenic scores that are the genome-wide cumulative sum from a GWAS; a polygenic score is then correlated with the other trait of interest. Genetic research of gender diversity has been limited and underpowered for gene discovery [16, 17].…”