Genome-Wide Linkage Study Meta-Analysis of Male Sexual Orientation

Alan R Sanders,Judith A Badner,Gary W Beecham,Brian S Mustanski,Shengru Guo,Eden R Martin,Sven Bocklandt,Dean H Hamer

doi:10.1007/s10508-021-02035-3

Abstract

Male sexual orientation is a scientifically and socially important trait shown by family and twin studies to be influenced by environmental and complex genetic factors. Individual genome-wide linkage studies (GWLS) have been conducted, but not jointly analyzed. Two main datasets account for > 90% of the published GWLS concordant sibling pairs on the trait and are jointly analyzed here: MGSOSO (Molecular Genetic Study of Sexual Orientation; 409 concordant sibling pairs in 384 families, Sanders et al. (2015)) and Hamer (155 concordant sibling pairs in 145 families, Mustanski et al. (2005)). We conducted multipoint linkage analyses with Merlin on the datasets separately since they were genotyped differently, integrated genetic marker positions, and combined the resultant LOD (logarithm of the odds) scores at each 1 cM grid position. We continue to find the strongest linkage support at pericentromeric chromosome 8 and chromosome Xq28. We also incorporated the remaining published GWLS dataset (on 55 families) by using meta-analytic approaches on published summary statistics. The meta-analysis has maximized the positional information from GWLS of currently available family resources and can help prioritize findings from genome-wide association studies (GWAS) and other approaches. Although increasing evidence highlights genetic contributions to male sexual orientation, our current understanding of contributory loci is still limited, consistent with the complexity of the trait. Further increasing genetic knowledge about male sexual orientation, especially via large GWAS, should help advance our understanding of the biology of this important trait.

Highlights

Male homosexuality runs in families, and twin studies have shown that genetic contributions appear to account for a moderate proportion of the variation in male sexual orientation with heritability estimated at ~ 32%
The Hamer dataset consisted of 441 individuals in 145 families genotyped with 408 short tandem repeat polymorphism genetic markers (STRPs) (Mustanski et al, 2005), and the MGSOSO dataset consisted of 908 individuals in 384 families and genotyped with 45,387 single-nucleotide polymorphism genetic markers (SNPs) (Sanders et al, 2015)
We found the genetic positions of the respective markers in the Rutgers Map v.3 (Nato et al, 2018) and used the nonparametric S-pairs and grid 1 cM options to perform multipoint linkage on both data sets, followed by combining LOD scores at each grid position across the marker sets

Summary

Introduction

Male homosexuality runs in families, and twin studies have shown that genetic contributions appear to account for a moderate proportion of the variation in male sexual orientation with heritability estimated at ~ 32% (for review, see Bailey et al, 2016). Three genome-wide linkage studies (GWLS) have been conducted on male sexual orientation, all focusing on concordant sibling pairs (2010homosexual brothers)— we refer here to these GWLS datasets as Hamer (Mustanski et al, 2005), MGSOSO (Molecular Genetic Study of Sexual Orientation) (Sanders et al, 2015), and Canadian (Ramagopalan et al, ). The MGSOSO performed a GWLS on 409 independent concordant sibling pairs in 384 families, making its strongest finding of significant (Lander & Kruglyak, 1995) linkage at pericentromeric chromosome 8 and detecting suggestive (Lander & Kruglyak, 1995) linkage (supportive evidence of previous findings) at chromosome Xq28 (Sanders et al, 2015). In order to extract the maximal positional information from GWLS of currently available family resources, we jointly analyzed the Hamer and MGSOSO datasets (and included the Canadian dataset by meta-analyzing published summary statistics)

Methods

Results

Conclusion