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

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.

SUBMITTER: Morris JA

PROVIDER: S-EPMC6358485 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Morris John A JA Kemp John P JP Youlten Scott E SE Laurent Laetitia L Logan John G JG Chai Ryan C RC Vulpescu Nicholas A NA Forgetta Vincenzo V Kleinman Aaron A Mohanty Sindhu T ST Sergio C Marcelo CM Quinn Julian J Nguyen-Yamamoto Loan L Luco Aimee-Lee AL Vijay Jinchu J Simon Marie-Michelle MM Pramatarova Albena A Medina-Gomez Carolina C Trajanoska Katerina K Ghirardello Elena J EJ Butterfield Natalie C NC Curry Katharine F KF Leitch Victoria D VD Sparkes Penny C PC Adoum Anne-Tounsia AT Mannan Naila S NS Komla-Ebri Davide S K DSK Pollard Andrea S AS Dewhurst Hannah F HF Hassall Thomas A D TAD Beltejar Michael-John G MG Adams Douglas J DJ Vaillancourt Suzanne M SM Kaptoge Stephen S Baldock Paul P Cooper Cyrus C Reeve Jonathan J Ntzani Evangelia E EE Evangelou Evangelos E Ohlsson Claes C Karasik David D Rivadeneira Fernando F Kiel Douglas P DP Tobias Jonathan H JH Gregson Celia L CL Harvey Nicholas C NC Grundberg Elin E Goltzman David D Adams David J DJ Lelliott Christopher J CJ Hinds David A DA Ackert-Bicknell Cheryl L CL Hsu Yi-Hsiang YH Maurano Matthew T MT Croucher Peter I PI Williams Graham R GR Bassett J H Duncan JHD Evans David M DM Richards J Brent JB

Nature genetics 20181231 2

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 stren ...[more]

PMID: 30598549

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Project description:Exercise, decompensated heart failure, and exposure to high altitude have been shown to cause symptoms of pulmonary edema in some, but not all, subjects, suggesting a genetic component to this response. Epithelial Na(+) Channels (ENaC) regulate Na(+) and fluid reabsorption in the alveolar airspace in the lung. An increase in number and/or activity of ENaC has been shown to increase lung fluid clearance. Previous work has demonstrated common functional genetic variants of the α-subunit of ENaC, including an A→T substitution at amino acid 663 (αA663T). We sought to determine the influence of the T663 variant of αENaC on lung diffusion at rest and at peak exercise in healthy humans. Thirty healthy subjects were recruited for study and grouped according to their SCNN1A genotype [n=17 vs. 13, age=25±7 years vs. 30±10 years, BMI=23±4 kg/m(2) vs. 25±4 kg/m(2), V(O2 peak) = 95±30%pred. vs. 100±31%pred., mean±SD, for AA (homozygous for αA663) vs. AT/TT groups (at least one αT663), respectively]. Measures of the diffusing capacity of the lungs for carbon monoxide (DL(CO)), the diffusing capacity of the lungs for nitric oxide (DL(NO)), alveolar volume (V(A)), and alveolar-capillary membrane conductance (D(M)) were taken at rest and at peak exercise. Subjects expressing the AA polymorphism of ENaC showed a significantly greater percent increase in DL(CO) and DL(NO), and a significantly greater decrease in systemic vascular resistance from rest to peak exercise than those with the AT/TT variant (DL(CO)=51±12% vs. 36±17%, DL(NO)=51±24% vs. 32±25%, SVR=-67±3 vs. -50±8%, p<0.05). The AA ENaC group also tended to have a greater percent increase in DL(CO)/VA from rest to peak exercise, although this did not reach statistical significance (49±26% vs. 33±26%, p=0.08). These results demonstrate that genetic variation of the α-subunit of ENaC at amino acid 663 influences lung diffusion at peak exercise in healthy humans, suggesting differences in alveolar Na(+) and, therefore, fluid handling. These findings could be important in determining who may be susceptible to pulmonary edema in response to various clinical or environmental conditions.

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

Publications

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

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