Sexual dimorphism in various bone phenotypes, including bone mineral
density (BMD), is widely observed; however, the extent to which genes
explain these sex differences is unclear. To identify variants with
different effects by sex, we examined gene-by-sex autosomal interactions
genome-wide, and performed expression quantitative trait loci (eQTL)
analysis and bioinformatics network analysis. We conducted an autosomal
genome-wide meta-analysis of gene-by-sex interaction on lumbar spine
(LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In
a second stage, we followed up the 12 top single-nucleotide
polymorphisms (SNPs; p?<?1?X?10-5) in an additional set of 24,763
individuals. Gene-by-sex interaction and sex-specific effects were
examined in these 12 SNPs. We detected one novel genome-wide significant
interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near
the GRM7 gene (male effect?=?0.02 and p?=?3.0?X?10-5; female
effect?=?-0.007 and p?=?3.3?X?10-2), and 11 suggestive loci associated
with either FN- or LS-BMD in discovery cohorts. However, there was no
evidence for genome-wide significant (p?<?5?X?10-8) gene-by-sex
interaction in the joint analysis of discovery and replication cohorts.
Despite the large collaborative effort, no genome-wide significant
evidence for gene-by-sex interaction was found to influence BMD
variation in this screen of autosomal markers. If they exist,
gene-by-sex interactions for BMD probably have weak effects, accounting
for less than 0.08% of the variation in these traits per implicated
SNP. (c) 2012 American Society for Bone and Mineral Research
