Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2017-09-04
Date Acceptance
2017-08-11
Citation
Nature Genetics, 2017, 49, pp.1468-1475
ISSN
1061-4036
Publisher
Nature Publishing Group
Start Page
1468
End Page
1475
Journal / Book Title
Nature Genetics
Volume
49
Copyright Statement
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
Sponsor
Wellcome Trust
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/28869591
PII: ng.3949
Grant Number
101123/Z/13/A
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GENOME-WIDE ASSOCIATION
HIGH-TRAUMA FRACTURES
LD SCORE REGRESSION
QUANTITATIVE ULTRASOUND
MENDELIAN RANDOMIZATION
OLDER WOMEN
MOUSE
RISK
GWAS
HERITABILITY
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
Calcaneus
Femur
Osteoclasts
Osteoblasts
Osteocytes
Animals
Mice, Knockout
Humans
Mice
Osteochondrodysplasias
Osteoporosis
Disease Models, Animal
Growth Disorders
Gene Expression Profiling
Bone Density
Phenotype
Polymorphism, Single Nucleotide
Female
Male
Glypicans
Genome-Wide Association Study
Molecular Sequence Annotation
06 Biological Sciences
11 Medical and Health Sciences
Developmental Biology
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2017-09-04