Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass.
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.


BACKGROUND
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.


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.
Ioannidis
John Pa
JP
Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.|Biomedical Research Institute, Foundation for Research and Technology-Hellas (FORTH), Ioannina, Greece.|Institute for Clinical Research and Health Policy Studies, Department of Medicine, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.
Ng
Mandy Y
MY
Genome Research Center, The University of Hong Kong, Hong Kong, China.|Department of Medicine, The University of Hong Kong and Queen Mary Hospital, Hong Kong, China.
Sham
Pak C
PC
Genome Research Center, The University of Hong Kong, Hong Kong, China.|Institute of Psychiatry, King's College London, London, United Kingdom.
Zintzaras
Elias
E
Biomathematics Unit, University of Thessaly School of Medicine, Larissa, Greece.
Lewis
Cathryn M
CM
Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
Deng
Hong-Wen
HW
Osteoporosis Research Center, Creighton University, Omaha, Nebraska, USA.|College of Life Sciences, Hunan Normal University, Hunan, China.|Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri-Kansas City, Kansas City, Missouri, USA.
Econs
Michael J
MJ
Departments of Medicine and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Karasik
David
D
Hebrew SeniorLife and Harvard Medical School Division of Aging, Boston, Massachusetts, USA.
Devoto
Marcella
M
Division of Human Genetics, CHOP, Philadelphia, Pennsylvania, USA.
Kammerer
Candace M
CM
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Spector
Tim
T
Twin and Genetic Epidemiology Research Unit, St Thomas' Hospital, London, United Kingdom.
Andrew
Toby
T
Twin and Genetic Epidemiology Research Unit, St Thomas' Hospital, London, United Kingdom.
Cupples
L Adrienne
LA
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
Duncan
Emma L
EL
Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, the Churchill Hospital, Oxford, United Kingdom.
Foroud
Tatiana
T
Departments of Medicine and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Kiel
Douglas P
DP
Hebrew SeniorLife and Harvard Medical School Division of Aging, Boston, Massachusetts, USA.
Koller
Daniel
D
Departments of Medicine and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Langdahl
Bente
B
Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark.
Mitchell
Braxton D
BD
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Peacock
Munro
M
Departments of Medicine and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Recker
Robert
R
Osteoporosis Research Center, Creighton University, Omaha, Nebraska, USA.
Shen
Hui
H
Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri-Kansas City, Kansas City, Missouri, USA.
Sol-Church
Katia
K
Department of Biomedical Research, Nemours' Childrens Clinic, Wilmington, Delaware, USA.
Spotila
Loretta D
LD
ScienceScribe, Haddonfield, New Jersey, USA.
Uitterlinden
Andre G
AG
Departments of Medicine and Epidemiology and Biostatistics, Erasmus University, Rotterdam, Netherlands.
Wilson
Scott G
SG
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Kung
Annie Wc
AW
Department of Medicine, The University of Hong Kong and Queen Mary Hospital, Hong Kong, China.
Ralston
Stuart H
SH
Rheumatic Diseases Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, Scotland.
D015519:Bone Density / Q000235:genetics*; D002874:Chromosome Mapping; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D008297:Male; D040641:Quantitative Trait Loci; D012737:Sex Factors