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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.

Original publication

DOI

10.1038/ng.3949

Type

Journal article

Journal

Nat genet

Publication Date

10/2017

Volume

49

Pages

1468 - 1475

Keywords

Animals, Bone Density, Calcaneus, Disease Models, Animal, Female, Femur, Gene Expression Profiling, Genome-Wide Association Study, Glypicans, Growth Disorders, Humans, Male, Mice, Mice, Knockout, Molecular Sequence Annotation, Osteoblasts, Osteochondrodysplasias, Osteoclasts, Osteocytes, Osteoporosis, Phenotype, Polymorphism, Single Nucleotide