Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis

John P Kemp, John A Morris, Carolina Medina-Gomez, Vincenzo Forgetta, Nicole M Warrington, Scott E Youlten, Jie Zheng, Celia L Gregson, Elin Grundberg, Katerina Trajanoska, John G Logan, Andrea S Pollard, Penny C Sparkes, Elena J Ghirardello, Rebecca Allen, Victoria D Leitch, Natalie C Butterfield, Davide Komla-Ebri, Anne-Tounsia Adoum, Katharine F Curry, Jacqueline K White, Fiona Kussy, Keelin M Greenlaw, Changjiang Xu, Nicholas C Harvey, Cyrus Cooper, David J Adams, Celia M T Greenwood, Matthew T Maurano, Stephen Kaptoge, Fernando Rivadeneira, Jonathan H Tobias, Peter I Croucher, Cheryl L Ackert-Bicknell, J H Duncan Bassett, Graham R Williams, J Brent Richards, David M Evans

Nature Genetics 2017 September 4

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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