Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.
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We thank P. Sham for helpful discussions and M. Schull for assistance with high-performance computing. We thank research nurses and assistants at the Departments of Surgical and Medical Sciences, Uppsala University, Uppsala, Sweden, for large-scale collection of bone samples and culture of primary osteoblasts. This part of the work was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). We thank T. Winkler for invaluable technical support for the EasyStrata Software used in this study.
This work was supported by the Medical Research Council (Programme Grant MC_UU_12013/4 to D.M.E.), the Wellcome Trust (Strategic Award grant number 101123; project grant 094134; to G.R.W., J.H.D.B. and P.I.C.), the Netherlands Organization for Health Research and Development ZonMw VIDI 016.136.367 (funding to F.R., C.M.-G. and K.T.), the mobility stimuli plan of the European Union Erasmus Mundus Action 2: ERAWEB (programme funding to K.T.), NIAMS, NIH (AR060981 and AR060234 to C.L.A.-B.), the National Health and Medical Research Council (Early Career Fellowship APP1104818 to N.M.W.), the Swedish Research Council (funding to E.G.), the Réseau de Médecine Génétique Appliquée (RMGA; J.A.M.), the Fonds de Recherche du Québec–Santé (FRQS; J.A.M. and J.B.R.), the Natural Sciences and Engineering Research Council of Canada (C.M.T.G.), the J. Gibson and the Ernest Heine Family Foundation (P.I.C.), Arthritis Research UK (ref. 20000; to C.L.G.), the Canadian Institutes of Health Research (J.B.R.), the Jewish General Hospital (J.B.R.), and the Australian Research Council (Future Fellowship FT130101709 to D.M.E.).
This research was conducted using the UK Biobank Resource (application number 12703). Access to the UK Biobank study data was funded by the University of Queensland (Early Career Researcher Grant 2014002959 to N.M.W.).
Integrated supplementary information
UK Biobank study descriptives.
Association results for 307 conditionally independent SNPs that reached genome-wide significance in the UK Biobank eBMD GWAS.
Look-up of 307 conditionally independent genome-wide significant SNPs for eBMD in the previous GEFOS-seq study and association results for fracture in the UK Biobank study.
Look up of published genome-wide significant BMD variants in the UK Biobank GWAS (eBMD, fracture) and the GEFOS-seq study (FN-BMD, LS-BMD, FA-BMD).
Results of GWAS for genome-wide significant variants corrected for weight.
Results of the test for sex heterogeneity at 307 genome-wide significant SNPs.
Genetic correlation analyses using LD Hub.
Variant Effect Predictor annotations for predicted deleterious genome-wide significant coding SNPs.
Results from statistical fine-mapping of autosomal loci using FINEMAP, functional annotation using DNase I hypersensitivity site data from 115 cell types, CATO score annotation, and possible target genes identified from cis-eQTL analyses in 95 primary human osteoblasts.
Results from cis-eQTL analyses in 95 primary human osteoblasts.
DEPICT gene prioritization (FDR < 5%).
DEPICT MeSH tissue and cell-type annotation enrichment (FDR < 0.05).
MAGENTA gene set enrichment analysis.
Skeletal phenotype data from the International Mouse Phenotyping Consortium and Mouse Genome Informatics databases, and expression data from mouse osteoblasts, osteocytes and osteoclasts.
Mouse knockouts from the OBDC study and their mean scores on a variety of bone-related phenotypes.
Summary of the evidence implicating GPC6 in the pathophysiology of osteoporosis.
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