BoneKEy Reports | BoneKEy Watch

Gene-by-sex interaction effect on BMD proves elusive


In the first genome-wide association analysis to focus on SNP-by-sex interaction for various different bone mineral density (BMD) phenotypes, Liu et al. initially identified 12 SNP–sex interaction loci that appeared to have the potential to show genome-wide significance. This was done by conducting an autosomal genome-wide meta-analysis of gene-by-sex interaction linked with BMD at the lumbar spine and femoral neck.

The 12 SNPs included a novel genome-wide significant interaction that was associated with lumbar spine BMD near to the GRM7 gene at Chr3p26.1−p25.1 (male effect=0.02 and p=3.0 × 10−5; female effect=−0.007 and p=3.3 × 10−2 ). However, although the original identification was made in over 25,000 adult men and women, the results were not replicated using a second sample of just under 25,000 adults of both sexes.

The researchers then checked the SNP-by-sex interactions identified against the largest meta-analysis of genome-wide association studies done to date but did not find any significant associations.

Editor’s comment: Liu and colleagues report that, despite the large collaborative effort (more than 50,000 men and women), no genome-wide significant evidence for gene-by-sex interaction was found influencing BMD variation. This suggests that we need to look beyond differences in common autosomal SNPs and focus on coding and regulatory regions. More sexually dimorphic bone traits (such as bone geometry, microarchitecture, and fracture, per se), may be best explored by genome-wide interaction studies such as this.

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