Dataset Information

Integrative genomic analysis for the functional roles of ITPKC in bone mineral density.

ABSTRACT: Osteoporosis is defined by low bone mineral density (BMD), which is mainly due to the imbalances in osteoclast and osteoblast activity. Previous studies indicated that early activation of osteoclasts relies on calcium entry through store-operated calcium (SOC) entry, and several genes, including STIM1, ORAI1, and ITPKC, are known as key regulators of SOC entry. However, the relationships between STIM1, ORAI1, ITPKC, and human BMD are still unclear. In order to investigate the plausible associations between these genes and BMD, we conducted a meta-analysis of genes expression and BMD using the publicly available GEO database. We further recruited 1044 subjects and tested associations between polymorphisms in these genes and BMD. Clinical information (including age, sex, and BMI) was collected and used for the analysis. Our results indicated that ITPKC gene expression was significantly associated with BMD. Furthermore, we found that one ITPKC SNP (rs2607420) was significantly associated with lumbar spine BMD. Through bioinformatics analysis, rs2607420 was found to be very likely to participate in the regulation of ITPKC expression. Our findings suggest that ITPKC is a susceptibility gene for BMD, and rs2607420 may play an important role in the regulation of this gene.

SUBMITTER: Lu HF

PROVIDER: S-EPMC6265621 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Integrative genomic analysis for the functional roles of <i>ITPKC</i> in bone mineral density.

Lu Hsing-Fang HF Wong Henry Sung-Ching HS Chen Ben-Kuen BK Liao Hsien-Tzung HT Hsu Yu-Wen YW Ikegawa Shiro S Cho Er-Chieh EC Hung Kuo-Sheng KS Chang Wei-Chiao WC

Bioscience reports 20181130 6

Osteoporosis is defined by low bone mineral density (BMD), which is mainly due to the imbalances in osteoclast and osteoblast activity. Previous studies indicated that early activation of osteoclasts relies on calcium entry through store-operated calcium (SOC) entry, and several genes, including STIM1, ORAI1, and ITPKC, are known as key regulators of SOC entry. However, the relationships between <i>STIM1, ORAI1, ITPKC</i>, and human BMD are still unclear. In order to investigate the plausible as ...[more]

PMID: 30355649

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Project description:Aiming to identify more genomic loci associated with bone mineral density (BMD), we conducted a joint association analysis of 2 genome-wide association study (GWAS) by the integrative association method multi-trait analysis of GWAS (MTAG). The first one is the single GWAS of estimated heel BMD (eBMD) in the UK biobank (UKB) cohort (N = 426,824), and the second one is the GWAS meta-analysis of total body BMD (TB-BMD) in 66,628 participants from 30 studies. Approximate conditional association analysis was performed in the identified novel loci to identify secondary association signal. Statistical fine-mapping was conducted to prioritize plausible credible risk variants (CRVs). Candidate genes were prioritized based on the analyses of cis- expression quantitative trait locus (cis-eQTL) and cis-protein QTL (cis-pQTL) information as well as the functional category of the SNP. By integrating the information carried in over 490,000 participants, this largest joint analysis of BMD GWAS identified 12 novel genomic loci at the genome-wide significance level (GWS, p = 5.0 × 10-8), nine of which were for eBMD and four were for TB-BMD, explaining an additional 0.11 and 0.23% heritability for the two traits, respectively. These loci include 1p33 (lead SNP rs10493130, peBMD = 3.19 × 10-8), 5q13.2 (rs4703589, peBMD = 4.78 × 10-8), 5q31.3 (rs9324887, pTB-BMD = 1.36 × 10-9), 6p21.32 (rs6905837, peBMD = 3.32 × 10-8), 6q14.1 (rs10806234, peBMD = 2.63 × 10-8), 7q21.11 (rs10806234, pTB-BMD = 3.37 × 10-8), 8q24.12 (rs11995866, peBMD = 6.72 × 10-9), 12p13.31 (rs1639122, peBMD = 4.43 × 10-8), 12p12.1 (rs58489179, peBMD = 4.74 × 10-8), 12q24.23 (rs75499226, peBMD = 1.44 × 10-8), 19q13.31 (rs7255083, pTB-BMD = 2.18 × 10-8) and 22q11.23 (rs13056137, pTB-BMD = 2.54 × 10-8). All lead SNPs in these 12 loci are nominally significant in both original studies as well as consistent in effect direction between them, providing solid evidence of replication. Approximate conditional analysis identified one secondary signal in 5q13.2 (rs11738874, pconditional = 5.06 × 10-9). Statistical fine-mapping analysis prioritized 269 CRVs. A total of 65 candidate genes were prioritized, including those with known biological function to bone development (such as FGF1, COL11A2 and DEPTOR). Our findings provide novel insights into a better understanding of the genetic mechanism underlying bone development as well as candidate genes for future functional investigation.

Dataset Information

Integrative genomic analysis for the functional roles of ITPKC in bone mineral density.

Publications

Integrative genomic analysis for the functional roles of <i>ITPKC</i> in bone mineral density.

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