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 ∼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 3.72×10
−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 8.62×10
−3
and 2.44×10
−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 ∼0.6 kb apart from the most significant SNP detected in our GWAS (rs7595412), achieved a
p
value of 7.66×10
−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.