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