Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study.
Osteoporosis, the most prevalent metabolic bone disease among older people, increases risk for low trauma hip fractures (HF) that are associated with high morbidity and mortality. Hip bone size (BS) has been identified as one of the key measurable risk factors for HF. Although hip BS is highly genetically determined, genetic factors underlying the trait are still poorly defined. Here, we performed the first genome-wide association study (GWAS) of hip BS interrogating approximately 380,000 SNPs on the Affymetrix platform in 1,000 homogeneous unrelated Caucasian subjects, including 501 females and 499 males. We identified a gene, PLCL1 (phospholipase c-like 1), that had four SNPs associated with hip BS at, or approaching, a genome-wide significance level in our female subjects; the most significant SNP, rs7595412, achieved a p value of 3.72x10(-7). The gene's importance to hip BS was replicated using the Illumina genotyping platform in an independent UK cohort containing 1,216 Caucasian females. Two SNPs of the PLCL1 gene, rs892515 and rs9789480, surrounded by the four SNPs identified in our GWAS, achieved p values of 8.62x10(-3) and 2.44x10(-3), respectively, for association with hip BS. Imputation analyses on our GWAS and the UK samples further confirmed the replication signals; eight SNPs of the gene achieved combined imputed p values<10(-5) in the two samples. The PLCL1 gene's relevance to HF was also observed in a Chinese sample containing 403 females, including 266 with HF and 177 control subjects. A SNP of the PLCL1 gene, rs3771362 that is only approximately 0.6 kb apart from the most significant SNP detected in our GWAS (rs7595412), achieved a p value of 7.66x10(-3) (odds ratio = 0.26) for association with HF. Additional biological support for the role of PLCL1 in BS comes from previous demonstrations that the PLCL1 protein inhibits IP3 (inositol 1,4,5-trisphosphate)-mediated calcium signaling, an important pathway regulating mechanical sensing of bone cells. Our findings suggest that PLCL1 is a novel gene associated with variation in hip BS, and provide new insights into the pathogenesis of HF.
Liu
Yao-Zhong
YZ
School of Medicine, University of Missouri - Kansas City, Kansas City, Missouri, United States of America.
Wilson
Scott G
SG
Wang
Liang
L
Liu
Xiao-Gang
XG
Guo
Yan-Fang
YF
Li
Jian
J
Yan
Han
H
Deloukas
Panos
P
Soranzo
Nicole
N
Chinappen-Horsley
Usha
U
Chinnapen-Horsley
Usha
U
Cervino
Alessandra
A
Cervino
Alesandra
A
Williams
Frances M
FM
Xiong
Dong-Hai
DH
Zhang
Yin-Ping
YP
Jin
Tian-Bo
TB
Levy
Shawn
S
Papasian
Christopher J
CJ
Drees
Betty M
BM
Hamilton
James J
JJ
Recker
Robert R
RR
Spector
Tim D
TD
Deng
Hong-Wen
HW
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D015992:Body Mass Index; D049628:Body Size; D002681:China; D005260:Female; D050723:Fractures, Bone / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D010024:Osteoporosis / Q000209:etiology / Q000235:genetics; D010384:Pelvic Bones / Q000033:anatomy & histology*; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000378:metabolism*; D012307:Risk Factors; D006113:United Kingdom
D048868:Adaptor Proteins, Signal Transducing; D011994:Recombinant Proteins; C533045:magic-factor 1 protein, mouse
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