Meta-Analysis of Genome-Wide Scans Provides Evidence for Sex- and Site-Specific Regulation of Bone Mass
Year: 2006
Type: review
Abstract: UNLABELLED: Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner. INTRODUCTION: BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. MATERIALS AND METHODS: Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. RESULTS: For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct. CONCLUSIONS: This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.
DOI: 10.1359/jbmr.060806
Authors: John PA Ioannidis, Mandy Y Ng, Pak C Sham, Elias Zintzaras, Cathryn M Lewis, Hong-Wen Deng, Michael J Econs, David Karasik, Marcella Devoto, Candace M Kammerer, Tim Spector, Toby Andrew, L Adrienne Cupples, Emma L Duncan, Tatiana Foroud, Douglas P Kiel, Daniel Koller, Bente Langdahl, Braxton D Mitchell, Munro Peacock, Robert Recker, Hui Shen, Katia Sol-Church, Loretta D Spotila, Andre G Uitterlinden, Scott G Wilson, Annie WC Kung, Stuart H Ralston
Institutions: Tufts University, Tufts Medical Center, University of Ioannina, Foundation for Research and Technology Hellas, Queen Mary Hospital, University of Hong Kong, King's College London, University of Thessaly, Creighton University, Hunan Normal University, University of Missouri–Kansas City, Indiana University Indianapolis, Indiana University School of Medicine, Harvard University, Hebrew SeniorLife, Children's Hospital of Philadelphia, University of Pittsburgh, St Thomas' Hospital, Boston University, Churchill Hospital, Oxford Centre for Diabetes, Endocrinology and Metabolism, Aarhus University Hospital, University of Maryland, Baltimore, Nemours Children’s Clinic, Erasmus University Rotterdam, Sir Charles Gairdner Hospital, Western General Hospital
Language: English
Subfield: Orthopedics and Sports Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Energy, Wellcome Trust, University of Southampton, University College London, European Commission, University of Glasgow, University of Aberdeen, National Natural Science Foundation of China, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources
Awards: GENETIC OF BONE STRUCTURAL GEOMETRY: FRAMINGHAM COHORTS, GENETIC LINKAGE TO LOW PEAK BONE MASS, G250621538, G2681271563, General Clinical Research Center, G319540772, Genetics of Atherosclerosis in Mexican Americans, G427003618, G5164707915, CHARACTERIZATION OF DELETERIOUS GENOMIC MUTATIONS, Genetics of Bone Density in Mexican Americans, Identification and characterization of genes involved in osteoporosis, THE FRAMINGHAM HEART STUDY-N01HC25195-268025195-268025195, Mid-Atlantic Nutrition Obesity Research Center, Inherited susceptibility to hip fracture, G7332241324, Genetic Basis of Osteoporotic Fractures and Bone Mass, Fundamental Investigations of Water Splitting on Model TiO2 (Kimmel's BES WBS04 of Henderson's BES-Hydrogen, PNNL Scope #48526), Genetic Determinants of Bone Fragility, G9000124674, G9000228098, Novel Molecular Biomarkers of Bone Microarchitecture, G956266236
OpenAlex ID: W2146114310