Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 34, Issue 7, Pages 1284-1296Publisher
WILEY
DOI: 10.1002/jbmr.3698
Keywords
HIP BONE GEOMETRY; FRACTURE; GENOMEWIDE ASSOCIATION STUDY; META-ANALYSIS; CANDIDATE GENES; POLYMORPHISMS
Categories
Funding
- NIH [R01 AR046838, R01 HD012252, R01 AR052147]
- Mid-Atlantic Nutrition and Obesity Research Center of Maryland [P30 DK072488]
- NIH/NIAMS [F32AR059469]
- American Heart Association [10SDG2690004]
- NHLBI [N01-HC- 85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, HL080295, HL087652, HL105756, HL103612, HL130114]
- NINDS
- NIA [AG-023629, AG-15928, AG-20098, AG-027058, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]
- National Center for Research Resources [UL1RR033176]
- National Center for Advancing Translational Sciences, CTSI [UL1TR001881]
- National Institute of Diabetes and Digestive and Kidney Disease [DK063491]
- US National Institute for Arthritis, Musculoskeletal and Skin Diseases
- National Institute on Aging [R01 AR41398, U24AG051129, R01 AR057118, R01 AR061162, R01 AR050066, R01 AR061445]
- Israel Science Foundation [1283/14, 994/10]
- National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]
- Affymetrix, Inc. [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
- Boston Medical Center
- Genome Quebec
- Genome Canada
- Canadian Institutes of Health Research (CIHR)
- Swedish Research Council
- Swedish Foundation for Strategic Research
- ALF/LUA research grant in Gothenburg
- Lundberg Foundation
- Emil and Vera Cornell Foundation
- Torsten and Ragnar Soderberg's Foundation
- Petrus and Augusta Hedlunds Foundation
- Vastra Gotaland Foundation
- Goteborg Medical Society
- German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015 G]
- National Institutes of Aging
- National Institutes of Health [HHSN268200782096C, R01 AG041517, 5UL1TR001108]
- Intramural Research Program of the NIH, National Library of Medicine
- Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]
- Genetic Laboratory of the Department of Internal Medicine
- Erasmus MC
- Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]
- Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]
- Netherlands Organization for Health Research and Development ZonMw [VIDI 016.136.367]
- Erasmus Medical Center
- Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Wellcome Trust
- Arthritis Research UK
- Chronic Disease Research Foundation
- Canadian Institutes of Health Research
- European Society for Clinical and Economic Aspects of Osteoporosis
- European Union FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]
- National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award
- Australian National Health and Medical Research Council (NHMRC) [1048216, 1127156]
- Wellcome Trust [WT092830M, WT088806, WT102215/2/13/2, 102215/2/13/2]
- UK Medical Research Council [G1001357]
- University of Bristol
- deCODE Genetics, ehf
- Swedish Research Council [K2015-52X-14691-13-4]
- Greta and Johan Kock Foundation
- A. Pahlsson Foundation
- A. Osterlund Foundation
- H Jarnhardt foundation
- King Gustav V and Queen Victoria Foundation
- Ake Wiberg Foundation
- Swedish Rheumatism Association
- Skane University Hospital Research Fund
- Research and Development Council of Region Skane, Sweden
- National Institutes of Health
- National Institute on Aging (NIA) [R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [RC2ARO58973]
- Harvard University Milton Fund
- NSF [BCS-1518596]
- NIH NIAMS [1R01AR070139-01A1]
- South East Norway Health Authority [52009/8029]
- 6th EU framework program [LSHM-CT-2003-502941]
- Oslo University Hospital, Ullevaal [52009/8029]
- Lovisenberg Diakonale Hospital
- [HHSN268201200036C]
Ask authors/readers for more resources
Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with similar to 2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p <= 2.6 x 10(-8)) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 x 10(-5)). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. (c) 2019 American Society for Bone and Mineral Research.
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