Format

Send to

Choose Destination
Nat Genet. 2017 Oct;49(10):1468-1475. doi: 10.1038/ng.3949. Epub 2017 Sep 4.

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

Author information

1
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
2
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
3
Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
4
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
5
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
6
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
7
Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, Western Australia, Australia.
8
Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
9
St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
10
Musculoskeletal Research Unit, Department of Translational Health Sciences, University of Bristol, Bristol, UK.
11
Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK.
12
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
13
Donnelly Center for Cellular and Biomedical Research, University of Toronto, Toronto, Ontario, Canada.
14
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
15
NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.
16
NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
17
Gerald Bronfman Department of Oncology, McGill University, Montréal, Québec, Canada.
18
Department of Epidemiology, Biostatistics &Occupational Health, McGill University, Montréal, Québec, Canada.
19
Department of Pathology and Institute for Systems Genetics, New York University Langone Medical Center, New York, New York, USA.
20
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
21
Strangeways Research Laboratory, Cambridge, UK.
22
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
23
Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, New York, USA.
24
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Abstract

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.

PMID:
28869591
PMCID:
PMC5621629
DOI:
10.1038/ng.3949
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Supplementary concept, Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center