Identifying causes of fracture beyond bone mineral density: evidence from human genetics

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Lu, Tianyuan^1,2; Forgetta, Vincenzo¹; Greenwood, Celia M. T.^1,3,4,5; Richards, J. Brent^1,5,6

Identifying causes of fracture beyond bone mineral density: evidence from human genetics

J Bone Miner Res. August 2022;37(8):1592-1602

©2022 American Society for Bone and Mineral Research (ASBMR)

Affiliations

¹Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada

²Quantitative Life Sciences Program, McGill University, Montreal, Canada

³Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada

⁴Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada

⁵Department of Human Genetics, McGill University, Montreal, Canada

⁶Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
Abstract and keywords

New therapies may help to prevent osteoporotic fractures other than through increasing bone mineral density (BMD). Because fracture risk has an important genetic component, we aim to identify loci increasing fracture risk that do not decrease BMD, using a recently-proposed structural equation model adapted to remove genetic influences of BMD on fracture risk. We used summary statistics of the largest genome-wide association studies (GWASs) for BMD and for fracture in these analyses. We next estimated the genetic correlation between the non-BMD or BMD-related genetic effects and other clinical risk factors for fracture. Last, based on white British participants in the UK Biobank, we conducted genetic risk score analyses to assess whether the aggregated genetic effects conferred increased major osteoporotic fracture risk. We found that only three loci affecting fracture risk exhibited genetic effects not mediated by BMD: SOST, CPED1-WNT16, and RSPO3, while these three loci simultaneously conferred BMD-related effects. No strong genetic associations between non-BMD or BMD-related effects and 16 clinical risk factors were observed. However, non-BMD effects might be genetic correlated with hip bone size. In the UK Biobank, a 1 standard deviation (1-SD) increase in the non-BMD genetic risk score conferred an odds ratio of 1.17 for incident major osteoporotic fracture, compared to 1.29 by a BMD-related genetic risk score. Our study suggests that the majority of common genetic predisposition toward fracture risk acts upon BMD. Although non-BMD genetic effects may exist, they are not strongly correlated with most traditional clinical risk factors. Risk loci harboring non-BMD genetic effects may influence other perspectives of bone quality, or confer effects that existing GWASs fail to capture, but they demonstrate weaker impact on fracture risk than BMD-related genetic effects. These findings suggest that most successful drug development programs for osteoporosis should focus on pathways identified through BMD-associated loci.

Keywords: BONE MINERAL DENSITY; FRACTURE; GENOME-WIDE ASSOCIATION STUDIES; RISK FACTORS; GENETIC DETERMINANTS
Links

DOI: 10.1002/jbmr.4632

PubMed: 35689460

WoS: 000817321000001
History

Received: 2021-09-07

Revised: 2022-05-28

Accepted: 2022-06-04

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Cited By (1)

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2023	Lu T, Forgetta V, Zhou S, Richards JB, Greenwood CMT. Identifying rare genetic determinants for improved polygenic risk prediction of bone mineral density and fracture risk. J Bone Miner Res. December 2023;38(12):1771-1781.