An atlas of genetic influences on osteoporosis in humans and mice.

Document Type

Article

Publication Date

2-2019

Identifier

DOI: 10.1038/s41588-018-0302-x; PMCID: PMC6358485

Abstract

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

Journal Title

Nature genetics

Volume

51

Issue

2

First Page

258

Last Page

266

MeSH Keywords

Adult; Aged; Animals; Bone Density; Female; Fractures, Bone; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Mice; Mice, Knockout; Middle Aged; Osteoporosis; Phenotype; Polymorphism, Single Nucleotide

Keywords

Animals; Bone Density; Bone Fractures; Genetic Predisposition to Disease; Genome-Wide Association Study; Mice; Osteoporosis; Phenotype; Single Nucleotide Polymorphism

Comments

Grant support

Erratum in

  • Author Correction: An atlas of genetic influences on osteoporosis in humans and mice. Morris JA, Kemp JP, Youlten SE, Laurent L, Logan JG, Chai RC, Vulpescu NA, Forgetta V, Kleinman A, Mohanty ST, Sergio CM, Quinn J, Nguyen-Yamamoto L, Luco AL, Vijay J, Simon MM, Pramatarova A, Medina-Gomez C, Trajanoska K, Ghirardello EJ, Butterfield NC, Curry KF, Leitch VD, Sparkes PC, Adoum AT, Mannan NS, Komla-Ebri DSK, Pollard AS, Dewhurst HF, Hassall TAD, Beltejar MG; 23andMe Research Team, Adams DJ, Vaillancourt SM, Kaptoge S, Baldock P, Cooper C, Reeve J, Ntzani EE, Evangelou E, Ohlsson C, Karasik D, Rivadeneira F, Kiel DP, Tobias JH, Gregson CL, Harvey NC, Grundberg E, Goltzman D, Adams DJ, Lelliott CJ, Hinds DA, Ackert-Bicknell CL, Hsu YH, Maurano MT, Croucher PI, Williams GR, Bassett JHD, Evans DM, Richards JB.Nat Genet. 2019 May;51(5):920. doi: 10.1038/s41588-019-0415-x.PMID: 30988516

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