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Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study
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2018 (English)In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 362, article id k3225Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2018. Vol. 362, article id k3225
National Category
Orthopaedics
Identifiers
URN: urn:nbn:se:umu:diva-151426DOI: 10.1136/bmj.k3225ISI: 000445701700002PubMedID: 30158200OAI: oai:DiVA.org:umu-151426DiVA, id: diva2:1244723
Funder
NIH (National Institute of Health), N01AG-12100Swedish Research Council, K2010-54X-09894-19-3Swedish Research Council, 2006-3832Swedish Research Council, K2010-52X-20229-05-3Swedish Foundation for Strategic Research Torsten Söderbergs stiftelseRagnar Söderbergs stiftelseRegion Västra GötalandNIH (National Institute of Health), U01 AR45580NIH (National Institute of Health), U01 AR45614NIH (National Institute of Health), U01 AR45632NIH (National Institute of Health), U01 AR45647NIH (National Institute of Health), U01 AR45654NIH (National Institute of Health), U01 AR45583NIH (National Institute of Health), U01 AG18197NIH (National Institute of Health), U01-AG027810NIH (National Institute of Health), UL1 RR024140Wellcome trust, 101123Wellcome trust, 110141Wellcome trust, 094134Forte, Swedish Research Council for Health, Working Life and WelfareThe Kempe Foundations, JCK-1021Västerbotten County Council, SpjutspetsanslagVLL: 159: 33-2007Available from: 2018-09-03 Created: 2018-09-03 Last updated: 2019-06-12Bibliographically approved

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Pettersson-Kymmer, Ulrika

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