Assessment of gene-by-sex interaction effect on bone mineral density

Abstract

Background 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 eQTL analysis and bioinformatics network analysis. Methods 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 eight cohorts. In a second stage, we followed up the 12 top SNPs (P<1×10−5) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. Results 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 & p-value = 3.0×10−5; female effect = −0.007 & p-value=3.3×10−2) and eleven suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (P<5×10−8) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Conclusion Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found influencing 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.

Integrating GWAS and Co-expression Network Data Identifies Bone Mineral Density Genes SPTBN1 and MARK3 and an Osteoblast Functional Module

“…In mice sexually dimporphic effects of genetic perturbations is common (as an example (Mesner et al, 2014)). In humans, however, there is little evidence that genetic effects on BMD differ between sexes (Liu et al, 2012a). There are many potential explanations as to why global knockouts in mice show sexually dimorphic effects on bone.…”

Heritability and Genetic Correlations for Bone Microarchitecture: The Framingham Study Families

“…First, although our sample was substantial, with up to 1047 phenotyped participants, the sample size was still too modest to allow stratification by sex or by age. We recognize that there might be sex- and age-specific genetic signals on bone microarchitecture (29) (similar to the aBMD (30) ), yet to be identified and validated. Second, we did not measure tibial aBMD, thus we cannot calculate genetic correlations between aBMD and HRpQCT measures at the tibia.…”

Genome-wide association meta-analyses to identify common genetic variants associated with hallux valgus in Caucasian and African Americans

“…p Values are estimated by Cochran's Q test 35. This Cochran's Q heterogeneity test in meta-analysis is equivalent to the traditional multivariate interaction model to test the SNP-by-sex interaction term in a general linear regression model.…”