Assessment of gene-by-sex interaction effect on bone mineral density.
Liu C-T., Estrada K., Yerges-Armstrong LM., Amin N., Evangelou E., Li G., Minster RL., Carless MA., Kammerer CM., Oei L., Zhou Y., Alonso N., Dailiana Z., Eriksson J., García-Giralt N., Giroux S., Husted LB., Khusainova RI., Koromila T., Kung AW., Lewis JR., Masi L., Mencej-Bedrac S., Nogues X., Nogues X., Patel MS., Prezelj J., Richards JB., Sham PC., Spector T., Vandenput L., Xiao S-M., Zheng H-F., Zhu K., Balcells S., Brandi ML., Frost M., Goltzman D., González-Macías J., Karlsson M., Khusnutdinova EK., Kollia P., Langdahl BL., Ljunggren O., Lorentzon M., Marc J., Mellström D., Ohlsson C., Olmos JM., Ralston SH., Riancho JA., Rousseau F., Urreizti R., Van Hul W., Zarrabeitia MT., Castano-Betancourt M., Demissie S., Grundberg E., Herrera L., Kwan T., Medina-Gómez C., Pastinen T., Sigurdsson G., Thorleifsson G., Vanmeurs JB., Blangero J., Hofman A., Liu Y., Mitchell BD., O'Connell JR., Oostra BA., Rotter JI., Stefansson K., Streeten EA., Styrkarsdottir U., Thorsteinsdottir U., Tylavsky FA., Uitterlinden A., Cauley JA., Harris TB., Ioannidis JP., Psaty BM., Robbins JA., Zillikens MC., Vanduijn CM., Prince RL., Karasik D., Rivadeneira F., Kiel DP., Cupples LA., Hsu Y-H.
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 × 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 × 10(-5) ; female effect = -0.007 and p = 3.3 × 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 × 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. © 2012 American Society for Bone and Mineral Research.