title: Genome-wide association study in East Asians suggests UHMK1 as a novel bone mineral density susceptibility gene.
abstract: To identify genetic variants that influence bone mineral density (BMD) in East Asians, we performed a quantitative trait analysis of lumbar spine, total hip and femoral neck BMD in a Korean population-based cohort (N=2729) and follow-up replication analysis in a Chinese Han population and two Caucasian populations (N=1547, 2250 and 987, respectively). From the meta-analysis of the stage 1 discovery analysis and stage 2 replication analysis, we identified four BMD loci that reached near-genome-wide significance level (P<5×10(-7)). One locus on 1q23 (UHMK1, rs16863247, P=4.1×10(-7) for femoral neck BMD and P=3.2×10(-6) for total hip BMD) was a novel BMD signal. Interestingly, rs16863247 was very rare in Caucasians (minor allele frequency<0.01), indicating that this association could be specific to East Asians. In gender specific analysis, rs1160574 on 1q32 (KCNH1) was associated with femoral neck BMD (P=2.1×10(-7)) in female subjects. rs9371538 in the known BMD region on 6q25 ESR1 was associated with lumbar spine BMD (P=5.6×10(-9)). rs7776725 in the known BMD region on 7q31 WTN16 was associated with total hip BMD (P=8.6×10(-9)). In osteoblasts, endogenous UHMK1 expression was increased during differentiation and UHMK1 knockdown decreased its differentiation, while UHMK1 overexpression increased its differentiation. In osteoclasts, endogenous UHMK1 expression was decreased during differentiation and UHMK1 knockdown increased its differentiation, while UHMK1 overexpression decreased its differentiation. In conclusion, our genome-wide association study identified the UHMK1 gene as a novel BMD locus specific to East Asians. Functional studies suggest a role of UHMK1 on regulation of osteoblasts and osteoclasts.
authors.affiliation: Department of Anatomy, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyung Jin
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyojung
authors.initials: H
authors.lastname: Park
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Jiangsu, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jung Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ye An
authors.initials: YA
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae-Yeon
authors.initials: JY
authors.lastname: Yang
authors.affiliation: Department of Epidemiology, School of Public Health, Soochow University, Jiangsu, PR China.
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Pei
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Cheongju, Republic of Korea.
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Hwang
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, USA.
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
authors.affiliation: Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Republic of Korea. Electronic address: chnaha@ajou.ac.kr.
authors.forename: Nam H
authors.initials: NH
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: csshin@snu.ac.kr.
authors.forename: Chan Soo
authors.initials: CS
authors.lastname: Shin
mesh_terms: D000328:Adult; D000818:Animals; D044466:Asian People / Q000235:genetics*; D015519:Bone Density / Q000235:genetics*; D002454:Cell Differentiation; D002460:Cell Line; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C530658:UHMK1 protein, human
keywords: BMD; East Asians; GWAS; UHMK1