Identification of the CACNA2D2 gene on chromosome 3p21 as a novel susceptibility gene for osteoporosis

Abstract

Evidence of linkage of chromosome 3p to bone mineral density (BMD) has been previously reported in individual as well as meta-analysis of genome wide linkage scans.To identify the quantitative trait loci gene underlying BMD variation at chromosome 3p, we performed a region-wide association study with 200 single-nucleotide polymorphisms (SNPs) across 6Mb of chromosome 3p21 in I, 243 case-control Chinese subjects.The cases were subjects with low BMD (Z-scores 5 -1.28, equivalent to the lowest 10 percent of the population) at either the L1-4 lumbar spine or femoral neck. Control subjects had high BMD (Z-score t +1.0) at the corresponding sites. Two hundred tag SNPs were selected and genotyped using the high-throughput Sequenom genotyping platform. One hundred thirty-five SNPs met quality control criteria (genotyping call rate 20.9. minor allele frequency 2 0.01, duplicate error rate <0.02 and Hardy-Weinberg equilibrium p values 20.01) and were analyzed for their association with BMD measured using dual- energy x-ray absorptiometry. Binary logistic regression analyses were performed to test for associations between each SNP genotype and BMD. Haplotype association analyses were performed by WHAP. Five SNPs (n11918619, n1471217, n2336664, rs7626551, and ~2257216) were associated with spine BMD and two SNPs (~2236953, rs2624839) with femoral neck BMD (p<O.OI) in single marker associations. The region that contained 6 SNPs, located within the CACNA2D2 gene, showed the strongest association with femoral neck BMD in the haplotype analyses (permutation p<0.002). In addition, we consistently detected significant associations for the haplotype CCGATGCCAC of the CACNA2D2 gene with BMD at the spine, trochanter and total hip region. Our results suggest that CACNAZD2, which encodes a voltage-dependent calcium channel subunit, is a novel susceptibility gene for BMD variation in Chinese and is likely to be involved in the pathogenesis of osteoporosis. Replication study is currently being conducted in Japanese population.