Assessment of the genetic and clinical determinants of fracture risk:​ genome wide association and mendelian randomisation study

Trajanoska, Katerina; Morris, John A.; Oei, Ling; Zheng, Hou-Feng; Evans, David M.; Kiel, Douglas P.; Ohlsson, Claes; Richards, J. Brent; Rivadeneira, Fernando

Affiliations

¹Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands

²Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, Netherlands

³Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada

⁴Department of Human Genetics, McGill University, Montréal, Québec, Canada

⁵DaP Lab, School of Life Sciences, Westlake University and Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China

⁶Institute of Aging Research and the Affiliated Hospital, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China

⁷Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK

⁸University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia

⁹Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA

¹⁰epartment of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

¹¹Centre for Bone and Arthritis Research, Department of Internal Medicine, Institute of Medicine, Sahlgrenska, Gothenburg, Sweden

Abstract

Objectives: To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk.

Design: Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach.

Setting: 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data.

Participants: A discovery set of 37 857 fracture cases and 227 116 controls; with replication in up to 147 200 fracture cases and 150 085 controls. Fracture cases were defined as individuals (>18 years old) who had fractures at any skeletal site confirmed by medical, radiological, or questionnaire reports. Instrumental variable analyses were performed to estimate effects of 15 selected clinical risk factors for fracture in a two-sample mendelian randomisation framework, using the largest previously published GWAS meta-analysis of each risk factor.

Results: Of 15 fracture associated loci identified, all were also associated with bone mineral density and mapped to genes clustering in pathways known to be critical to bone biology (eg, SOST, WNT16, and ESR1) or novel pathways (FAM210A, GRB10, and ETS2). Mendelian randomisation analyses showed a clear effect of bone mineral density on fracture risk. One standard deviation decrease in genetically determined bone mineral density of the femoral neck was associated with a 55% increase in fracture risk (odds ratio 1.55 (95% confidence interval 1.48 to 1.63; P=1.5×10⁻⁶⁸). Hand grip strength was inversely associated with fracture risk, but this result was not significant after multiple testing correction. The remaining clinical risk factors (including vitamin D levels) showed no evidence for an effect on fracture.

Conclusions: This large scale GWAS meta-analysis for fracture identified 15 genetic determinants of fracture, all of which also influenced bone mineral density. Among the clinical risk factors for fracture assessed, only bone mineral density showed a major causal effect on fracture. Genetic predisposition to lower levels of vitamin D and estimated calcium intake from dairy sources were not associated with fracture risk.

Links

DOI: 10.1136/bmj.k3225

PubMed: 30158200

WoS: 000445701700002

History

Accepted: 2018-07-02

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2020	Chen H, Shao Z, Gao Y, Yu X, Huang S, Zeng P. Are blood lipids risk factors for fracture? integrative evidence from instrumental variable causal inference and mediation analysis using genetic data. Bone. February 2020;131:115174.
2020	Bai W-Y, Wang L, Ying Z-M, Hu B, Xu L, Zhang G-Q, Cong P-K, Zhu X, Zou W, Zheng H-F. Identification of PIEZO1 polymorphisms for human bone mineral density. Bone. April 2020;133:115247.
2021	de Nigris F, Ruosi C, Colella G, Napoli C. Epigenetic therapies of osteoporosis. Bone. January 2021;142:115680.
2020	Tanaka K-i, Kanazawa I, Richards JB, Goltzman D, Sugimoto T. Modulators of Fam210a and roles of Fam210a in the function of myoblasts. Calcif Tiss Int. May 2020;106(5):533-540.
2021	Xiao X, Wu Q. The utility of genetic risk score to improve performance of FRAX for fracture prediction in US postmenopausal women. Calcif Tiss Int. June 2021;108(6):746-756.
2020	Keller‐Baruch J, Forgetta V, Manousaki D, Zhou S, Richards JB. Genetically decreased circulating vascular endothelial growth factor and osteoporosis outcomes: a mendelian randomization study. J Bone Miner Res. April 2020;35(4):649-656.
2020	Zheng J, Brion M, Kemp JP, Warrington NM, Borges M, Hemani G, Richardson TG, Rasheed H, Qiao Z, Haycock P, Ala‐Korpela M, Smith GD, Tobias JH, Evans DM. The effect of plasma lipids and lipid‐lowering interventions on bone mineral density: a Mendelian randomization study. J Bone Miner Res. July 2020;35(7):1224-1235.
2020	Kiel DP, Kemp JP, Rivadeneira F, Westendorf JJ, Karasik D, Duncan EL, Imai Y, Müller R, Flannick J, Bonewald L, Burtt N. The musculoskeletal knowledge portal: making omics data useful to the broader scientific community. J Bone Miner Res. September 2020;35(9):1626-1633.
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2022	Kasher M, Freidin MB, Williams FM, Cherny SS, Malkin I, Livshits G. Shared genetic architecture between rheumatoid arthritis and varying osteoporotic phenotypes. J Bone Miner Res. March 2022;37(3):440-453.
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2023	Tran TS, Ho-Le TP, Bliuc D, Center JR, Blank RD, Nguyen TV. Prevention of hip fractures: trade-off between minor benefits to individuals and large benefits to the community. J Bone Miner Res. November 2023;38(11):1594-1602.
2021	Zhang Q, Greenbaum J, Shen H, Zhao L-J, Zhang W-D, Sun C-Q, Deng H-W. Detecting causal relationship between metabolic traits and osteoporosis using multivariable Mendelian randomization. Osteoporos Int. April 2021;32(4):715-725.
2023	Nilsson K. NOTUM and RSPO3 in Bone: WNT Signaling Modulators Regulating the Skeleton [PhD thesis]. University of Gothenburg; 2023.
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