Abstract
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 ∼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 × 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 × 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1284-1296 |
| Number of pages | 13 |
| Journal | Journal of Bone and Mineral Research |
| Volume | 34 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2019 |
Keywords
- CANDIDATE GENES
- FRACTURE, GENOMEWIDE ASSOCIATION STUDY
- HIP BONE GEOMETRY
- META-ANALYSIS
- POLYMORPHISMS
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Orthopedics and Sports Medicine
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry. / Hsu, Yi Hsiang; Estrada, Karol; Evangelou, Evangelos et al.
In: Journal of Bone and Mineral Research, Vol. 34, No. 7, 07.2019, p. 1284-1296.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry
AU - Hsu, Yi Hsiang
AU - Estrada, Karol
AU - Evangelou, Evangelos
AU - Ackert-Bicknell, Cheryl
AU - Akesson, Kristina
AU - Beck, Thomas
AU - Brown, Suzanne J.
AU - Capellini, Terence
AU - Carbone, Laura
AU - Cauley, Jane
AU - Cheung, Ching Lung
AU - Cummings, Steven R.
AU - Czerwinski, Stefan
AU - Demissie, Serkalem
AU - Econs, Michael
AU - Evans, Daniel
AU - Farber, Charles
AU - Gautvik, Kaare
AU - Harris, Tamara
AU - Kammerer, Candace
AU - Kemp, John
AU - Koller, Daniel L.
AU - Kung, Annie
AU - Lawlor, Debbie
AU - Lee, Miryoung
AU - Lorentzon, Mattias
AU - McGuigan, Fiona
AU - Medina-Gomez, Carolina
AU - Mitchell, Braxton
AU - Newman, Anne
AU - Nielson, Carrie
AU - Ohlsson, Claes
AU - Peacock, Munro
AU - Reppe, Sjur
AU - Richards, J. Brent
AU - Robbins, John
AU - Sigurdsson, Gunnar
AU - Spector, Timothy D.
AU - Stefansson, Kari
AU - Streeten, Elizabeth
AU - Styrkarsdottir, Unnur
AU - Tobias, Jonathan
AU - Trajanoska, Katerina
AU - Uitterlinden, André
AU - Vandenput, Liesbeth
AU - Wilson, Scott G.
AU - Yerges-Armstrong, Laura
AU - Young, Mariel
AU - Zillikens, M. Carola
AU - Rivadeneira, Fernando
AU - Kiel, Douglas P.
AU - Karasik, David
N1 - Funding Information: Framingham Osteoporosis Study (FOS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR41398 and U24AG051129; DPK and R01 AR057118, R01 AR061162, R01 AR050066, and R01 AR061445). DK was also supported by Israel Science Foundation grant #1283/14. The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). Funding Information: Osteoporosis Prospective Risk Assessment study (OPRA): This work was supported by grants from the Swedish Research Council (K2015-52X-14691-13-4), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, the H J€arnhardt foundation, King Gustav V and Queen Victoria Foundation, Åke Wiberg Foundation, The Swedish Rheumatism Association, Skåne University Hospital Research Fund, Research and Development Council of Region Skåne, Sweden. Funding Information: Discovery Cohorts Old Order Amish (OOA): This work was supported by NIH research grant R01 AR046838. Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488). LMYA was supported by F32AR059469 from NIH/NIAMS. MF was supported by American Heart Association grant [10SDG2690004]. Funding Information: Twins UK (TUK): The study was funded by the Wellcome Trust, the Arthritis Research UK, the Chronic Disease Research Foundation, the Canadian Institutes of Health Research (J.B.R.), the European Society for Clinical and Economic Aspects of Osteoporosis (J.B.R.) and the European Union FP-5 GenomEUt-win Project (QLG2-CT-2002-01254). The study also received support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London. We thank the staff of the Twins UK study; the DNA Collections and Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation; Quality Control of the Twins UK cohort for genotyping (in particular A. Chaney, R. Ravindrarajah, D. Simpkin, C. Hinds and T. Dibling); P. Martin and S. Potter of the DNA and Genotyping Informatics teams for data handling; Le Centre National de Genotypage, France, led by M. Lathrop, for genotyping; Duke University, North Carolina, USA, led by D. Goldstein, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by A. Palotie. The study was also supported by Israel Science Foundation, grant number #994/10 and the Australian National Health and Medical Research Council (NHMRC) (Project Grants 1048216, 1127156). Replication Cohorts ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. ALSPAC data collection was supported by the Wellcome Trust (grants WT092830M; WT088806; WT102215/2/13/2), UK Medical Research Council (G1001357), and University of Bristol. The UK Medical Research Council and the Wellcome Trust (ref: 102215/ 2/13/2) and the University of Bristol provide core support for ALSPAC. deCODE Study: The study was funded by deCODE Genetics, ehf. We thank all the participants of this study, the staff of deCODE Genetics core facilities and recruitment center and the densitometry clinic at the University Hospital for their important contributions to this work. Funding Information: Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts 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, and by HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL130114 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881; in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Funding Information: Rotterdam II and III: Rotterdam Study (RS): See Discovery Cohort SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the SOF ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Functional Validation We thank Dr. Claire Reardon and the entire Harvard University Bauer Core facility for assistance with next generation sequencing. This work was funded in part by the Harvard University Milton Fund, NSF (BCS-1518596), and NIH NIAMS (1R01AR070139-01A1) to TDC. Funding Information: Indiana: We thank the individuals who participated in this study, as well as the study coordinators, without whom this work would not have been possible. This work was supported by National Institutes of Health grants R01 AG041517 and 5UL1TR001108. Genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Funding Information: Functional validation in humans was supported by the South East Norway Health Authority (52009/8029), the 6th EU framework program (LSHM-CT-2003-502941), Oslo University Hospital, Ullevaal (52009/8029) and Lovisenberg Diakonale Hospital to KMG and SR. Funding Information: Rotterdam Study (RSI, RSII, & RSIII): The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters, for their help in creating the GWAS database, and Yurii Aulchenko, PhD, for the creation of imputed data. We would like to thank Dr. Tobias A. Knoch, Marijn Verkerk, Anis Abuseiris, Dr. Linda Boer and Rob de Graaf (Erasmus MC Rotterdam, The Netherlands), for their help in creating and maintaining GRIMP. Dr. Fernando Rivadeneira received an additional grant from the Netherlands Organization for Health Research and Development ZonMw VIDI 016.136.367. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are very grateful to the study participants, the staff from the Rotterdam Study (particularly L. Buist and J.H. van den Boogert) and the participating general practitioners and pharmacists. Funding Information: Fels Longitudinal Study (FELS): The study was supported by NIH research grants, R01 HD012252 and R01 AR052147. The authors are thankful to the Fels Longitudinal Study participants for their long-term commitment to the study and to data collection staff at the Department of Population and Public Health Sciences, Boonshoft School of Medicine, Wright State University. Funding Information: Gothenburg Osteoporosis and Obesity Determinants Study (GOOD): The study was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, The ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Emil and Vera Cornell Foundation, the Torsten and Ragnar So€derberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the V€astra Go€taland Foundation, and the Go€teborg Medical Society. We would like to thank Dr. Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G for access to their grid resources. Funding Information: Health Aging and Body Composition Study (Health ABC): This study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were Publisher Copyright: © 2019 American Society for Bone and Mineral Research
PY - 2019/7
Y1 - 2019/7
N2 - 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 ∼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 × 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 × 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.
AB - 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 ∼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 × 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 × 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.
KW - CANDIDATE GENES
KW - FRACTURE, GENOMEWIDE ASSOCIATION STUDY
KW - HIP BONE GEOMETRY
KW - META-ANALYSIS
KW - POLYMORPHISMS
UR - http://www.scopus.com/inward/record.url?scp=85063162256&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063162256&partnerID=8YFLogxK
U2 - 10.1002/jbmr.3698
DO - 10.1002/jbmr.3698
M3 - Article
C2 - 30888730
AN - SCOPUS:85063162256
SN - 0884-0431
VL - 34
SP - 1284
EP - 1296
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 7
ER -