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

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

    Research output: Contribution to journalArticle

    31 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)2051-2064
    Number of pages14
    JournalJournal of Bone and Mineral Research
    Volume27
    Issue number10
    DOIs
    StatePublished - Oct 2012

    Keywords

    • AGING
    • ASSOCIATION
    • BMD
    • GENE-BY-SEX INTERACTION

    ASJC Scopus subject areas

    • Endocrinology, Diabetes and Metabolism
    • Orthopedics and Sports Medicine

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  • Cite this

    Liu, C. T., Estrada, K., Yerges-Armstrong, L. M., Amin, N., Evangelou, E., Li, G., Minster, R. L., Carless, M. A., Kammerer, C. M., Oei, L., Zhou, Y., Alonso, N., Dailiana, Z., Eriksson, J., García-Giralt, N., Giroux, S., Husted, L. B., Khusainova, R. I., Koromila, T., ... Hsu, Y. H. (2012). Assessment of gene-by-sex interaction effect on bone mineral density. Journal of Bone and Mineral Research, 27(10), 2051-2064. https://doi.org/10.1002/jbmr.1679