title: Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study.
abstract: 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.
authors.affiliation: School of Medicine, University of Missouri - Kansas City, Kansas City, Missouri, United States of America.
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Liu
authors.forename: Scott G
authors.initials: SG
authors.lastname: Wilson
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Xiao-Gang
authors.initials: XG
authors.lastname: Liu
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Guo
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Usha
authors.initials: U
authors.lastname: Chinappen-Horsley
authors.forename: Usha
authors.initials: U
authors.lastname: Chinnapen-Horsley
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cervino
authors.forename: Alesandra
authors.initials: A
authors.lastname: Cervino
authors.forename: Frances M
authors.initials: FM
authors.lastname: Williams
authors.forename: Dong-Hai
authors.initials: DH
authors.lastname: Xiong
authors.forename: Yin-Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Tian-Bo
authors.initials: TB
authors.lastname: Jin
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papasian
authors.forename: Betty M
authors.initials: BM
authors.lastname: Drees
authors.forename: James J
authors.initials: JJ
authors.lastname: Hamilton
authors.forename: Robert R
authors.initials: RR
authors.lastname: Recker
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: 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
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011994:Recombinant Proteins; C533045:magic-factor 1 protein, mouse
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