Identification of PLCL 1 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 ,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 genomewide significance level in our female subjects; the most significant SNP, rs7595412, achieved a p value of 3.72610. 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 8.62610 and 2.44610, 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 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 ,0.6 kb apart from the most significant SNP detected in our GWAS (rs7595412), achieved a p value of 7.66610 (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. Citation: Liu Y-Z, Wilson SG, Wang L, Liu X-G, Guo Y-F, et al. (2008) Identification of PLCL1 Gene for Hip Bone Size Variation in Females in a Genome-Wide Association Study. PLoS ONE 3(9): e3160. doi:10.1371/journal.pone. 0003160 Editor: Debbie Fox, The Research Institute for Children at Children’s Hospital New Orleans, United States of America Received June 25, 2008; Accepted August 18, 2008; Published September 8, 2008 Copyright: 2008 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Investigators of this work (Deng HW, Liu YZ, Wang L, Guo YF, Li J, Liu XG, Yan H, Xiong DH, Zhang YP, and Jing TB) were partially supported by grants from NIH (R01 AR050496-01, R21 AG027110, R01 AG026564, R21 AA015973 and P50 AR055081). The study also benefited from grants from National Science Foundation of China, Huo Ying Dong Education Foundation, HuNan Province, Xi’an Jiaotong University, and the Ministry of Education of China. Investigators from UK and Australia (Spector TD, Wilson SG, Deloukas P, Soranzo N, Chinnapen-Horsley U, Williams FM and Cervino A) were supported by Wellcome Trust; European Commission (QLK6-CT-2002-02629, GEFOS); the Arthritis Research Campaign; the Chronic Disease Research Foundation and the European Union FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the Australian National Health and Medical Research Council (Project Grants 294402 and 343603). Competing Interests: The authors have declared that no competing interests exist. * E-mail: dengh@umkc.edu