Assessment of gene-by-sex interaction effect on bone mineral density
Authors: Liu Ching-Ti , Estrada Karol , Yerges-Armstrong Laura M , Amin Najaf , Evangelou Evangelos , Li Guo , Minster Ryan L , Carless Melanie A , Kammerer Candace M , Oei Ling , Zhou Yanhua , Alonso Nerea , Dailiana Zoe , Eriksson Joel , García-Giralt Natalia , Giroux Sylvie , Husted Lise Bjerre , Khusainova Rita I , Koromila Theodora , Kung Annie WaiChee , Lewis Joshua R , Masi Laura , Mencej-Bedrac Simona , Nogues Xavier , Patel Millan S , Prezelj Janez , Richards J Brent , Sham Pak Chung , Spector Timothy , Vandenput Liesbeth , Xiao Su-Mei , Zheng Hou-Feng , Zhu Kun , Balcells Susana , Brandi Maria Luisa , Frost Morten , Goltzman David , González-Macías Jesús , Karlsson Magnus , Khusnutdinova Elza K , Kollia Panagoula , Langdahl Bente Lomholt , Ljunggren Östen , Lorentzon Mattias , Marc Janja , Mellström Dan , Ohlsson Claes , Olmos José M , Ralston Stuart H , Riancho José A , Rousseau François , Urreizti Roser , Van Hul Wim , Zarrabeitia María T , Castano-Betancourt Martha , Demissie Serkalem , Grundberg Elin , Herrera Lizbeth , Kwan Tony , Medina-Gómez Carolina , Pastinen Tomi , Sigurdsson Gunnar , Thorleifsson Gudmar , vanMeurs Joyce BJ , Blangero John , Hofman Albert , Liu Yongmei , Mitchell Braxton D , O'Connell Jeffrey R , Oostra Ben A , Rotter Jerome I , Stefansson Kari , Streeten Elizabeth A , Styrkarsdottir Unnur , Thorsteinsdottir Unnur , Tylavsky Frances A , Uitterlinden Andre , Cauley Jane A , Harris Tamara B , Ioannidis John PA , Psaty Bruce M , Robbins John A , Zillikens M Carola , vanDuijn Cornelia M , Prince Richard L , Karasik David , Rivadeneira Fernando , Kiel Douglas P , Cupples L Adrienne , Hsu Yi-Hsiang 
Published: June 2012

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 &lt; 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 &lt; 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.