Journal
NATURE GENETICS
Volume 49, Issue 10, Pages 1468-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3949
Keywords
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Categories
Funding
- Genome Quebec
- Genome Canada
- Canadian Institutes of Health Research (CIHR)
- Medical Research Council [MC_UU_12013/4]
- Wellcome Trust [101123, 094134]
- Netherlands Organization for Health Research and Development [ZonMw VIDI 016.136.367]
- NIAMS, NIH [AR060981, AR060234]
- National Health and Medical Research Council [APP1104818]
- Swedish Research Council
- Reseau de Medecine Genetique Appliquee
- Fonds de Recherche du Quebec-Sante
- Natural Sciences and Engineering Research Council of Canada
- Ernest Heine Family Foundation
- Arthritis Research UK [20000]
- Canadian Institutes of Health Research
- Jewish General Hospital
- Australian Research Council [FT130101709]
- University of Queensland [2014002959]
- mobility stimuli plan of the European Union Erasmus Mundus Action 2: ERAWEB
- British Heart Foundation [RG/13/13/30194, RG/08/014/24067] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [20000] Funding Source: researchfish
- Medical Research Council [U1475000002, MR/L003120/1, MC_UU_12011/1, MC_qA137853, MC_UP_A620_1014, MC_U147585827, MC_UU_12013/4, MC_U147585824, G0400491, MC_U147585819, U1475000001] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10082, 10/33/04, NF-SI-0512-10165, NF-SI-0513-10085] Funding Source: researchfish
- Australian Research Council [FT130101709] Funding Source: Australian Research Council
- MRC [MC_U147585819, MC_U147585827, MR/L003120/1, MC_UU_12013/4, G0400491] Funding Source: UKRI
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Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genomewide 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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