title: Genome-wide association meta-analyses identified 1q43 and 2q32.2 for hip Ward's triangle areal bone mineral density.
abstract: Aiming to identify genomic variants associated with osteoporosis, we performed a genome-wide association meta-analysis of bone mineral density (BMD) at Ward's triangle of the hip in 7175 subjects from 6 samples. We performed in silico replications with femoral neck, trochanter, and inter-trochanter BMDs in 6912 subjects from the Framingham heart study (FHS), and with forearm, femoral neck and lumbar spine BMDs in 32965 subjects from the GEFOS summary results. Combining the evidence from all samples, we identified 2 novel loci for areal BMD: 1q43 (rs1414660, discovery p=1.20×10(-8), FHS p=0.05 for trochanter BMD; rs9287237, discovery p=3.55×10(-7), FHS p=9.20×10(-3) for trochanter BMD, GEFOS p=0.02 for forearm BMD, nearest gene FMN2) and 2q32.2 (rs56346965, discovery p=7.48×10(-7), FHS p=0.10 for inter-trochanter BMD, GEFOS p=0.02 for spine BMD, nearest gene NAB1). The two lead SNPs rs1414660 and rs56346965 are eQTL sites for the genes GREM2 and NAB1 respectively. Functional annotation of GREM2 and NAB1 illustrated their involvement in BMP signaling pathway and in bone development. We also replicated three previously reported loci: 5q14.3 (rs10037512, discovery p=3.09×10(-6), FHS p=8.50×10(-3), GEFOS p=1.23×10(-24) for femoral neck BMD, nearest gene MEF2C), 6q25.1 (rs3020340, discovery p=1.64×10(-6), GEFOS p=1.69×10(-3) for SPN-BMD, nearest gene ESR1) and 7q21.3 (rs13310130, discovery p=8.79×10(-7), GEFOS p=2.61×10(-7) for spine BMD, nearest gene SHFM1). Our findings provide additional insights that further enhance our understanding of bone development, osteoporosis, and fracture pathogenesis.
authors.affiliation: Department of Epidemiology and Health Statistics, School of Public Health, Medical College of Soochow University, Jiangsu, PR China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Jiangsu, PR China.
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Pei
authors.affiliation: Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Jiangsu, PR China; Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Jiangsu, PR China.
authors.forename: Wen-Zhu
authors.initials: WZ
authors.lastname: Hu
authors.affiliation: Inner Mongolia Autonomous Region People's Hospital, Hohhot, Inner Mongolia, PR China.
authors.forename: Rong
authors.initials: R
authors.lastname: Hai
authors.affiliation: Inner Mongolia Autonomous Region People's Hospital, Hohhot, Inner Mongolia, PR China.
authors.forename: Xiu-Yan
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, PR China.
authors.forename: Shu
authors.initials: S
authors.lastname: Ran
authors.affiliation: Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Jiangsu, PR China; Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Jiangsu, PR China.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Lei
authors.affiliation: Department of Epidemiology and Health Statistics, School of Public Health, Medical College of Soochow University, Jiangsu, PR China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Jiangsu, PR China.
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Department of Basic Medical Science, University of Missouri-Kansas City, Kansas City, MO, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papasian
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA. Electronic address: hdeng2@tulane.edu.
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
authors.affiliation: Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Jiangsu, PR China; Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Jiangsu, PR China. Electronic address: lzhang6@suda.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000328:Adult; D015519:Bone Density / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006615:Hip / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results
keywords: Bone mineral density; GREM2; Genome-wide association study; Hip Ward's triangle; Meta-analysis; NAB1