Dataset Information

A genome-wide association study of copy-number variation identifies putative loci associated with osteoarthritis in Koreans.

ABSTRACT:

Background

OA is a complex disease caused by environmental and genetic risk factors. The purpose of this study is to identify candidate copy number variations (CNVs) associated with OA.

Methods

We performed a genome-wide association study of CNV to identify potential loci that confer susceptibility to or protection from OA. CNV genotyping was conducted using NimbleGen HD2 3 × 720K comparative hybridization array and included samples from 371 OA patients and 467 healthy controls. The putative CNV regions identified were confirmed with a TaqMan assay.

Results

We identified six genomic regions associated with OA encompassing CNV loci. None of six loci had previously been reported in genome-wide association studies with OA, although a genetic analysis suggested that they have functional effects. The protein product of a candidate risk gene for obesity, TNKS, targets Wnt inhibition, and this gene was significantly associated with hand and knee OA. Copy number deletion on TNKS was associated with a 1.37-fold decreased risk for OA. In addition, CA10, which shows a strong association with osteoporosis, was also significant in our study. Copy number deletion on this gene was associated with a 1.69-fold decreased risk for OA.

Conclusion

We identified several CNV loci that may contribute to OA susceptibility in Koreans. Further functional investigations of these genes are warranted to fully characterize their putative association.

SUBMITTER: Moon S

PROVIDER: S-EPMC4395893 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Publications

A genome-wide association study of copy-number variation identifies putative loci associated with osteoarthritis in Koreans.

Moon Sanghoon S Keam Bhumsuk B Hwang Mi Yeong MY Lee Young Y Park Suyeon S Oh Ji Hee JH Kim Yeon-Jung YJ Lee Heun-Sik HS Kim Nam Hee NH Kim Young Jin YJ Kim Dong-Hyun DH Han Bok-Ghee BG Kim Bong-Jo BJ Lee Juyoung J

BMC musculoskeletal disorders 20150404

<h4>Background</h4>OA is a complex disease caused by environmental and genetic risk factors. The purpose of this study is to identify candidate copy number variations (CNVs) associated with OA.<h4>Methods</h4>We performed a genome-wide association study of CNV to identify potential loci that confer susceptibility to or protection from OA. CNV genotyping was conducted using NimbleGen HD2 3 × 720K comparative hybridization array and included samples from 371 OA patients and 467 healthy controls. T ...[more]

PMID: 25880085

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Project description:BackgroundUlcerative colitis (UC), a complex polygenic disorder, is one of the main subphenotypes of inflammatory bowel disease. A comprehensive dissection of the genetic etiology of UC needs to assess the contribution of rare genetic variants including copy number variations (CNVs) to disease risk. In this study, we performed a multi-step genome-wide case-control analysis to interrogate the presence of disease-relevant rare copy number variants.MethodsOne thousand one hundred twenty-one German UC patients and 1770 healthy controls were initially screened for rare deletions and duplications employing SNP-array data. Quantitative PCR and high density custom array-CGH were used for validation of identified CNVs and fine mapping. Two main follow-up panels consisted of an independent cohort of 451 cases and 1274 controls, in which CNVs were assayed through quantitative PCR, and a British cohort of 2396 cases versus 4886 controls with CNV genotypes based on array data. Additional sample sets were assessed for targeted and in silico replication.ResultsTwenty-four rare copy number variants (14 deletions and 10 duplications), overrepresented in UC patients were identified in the initial screening panel. Follow-up of these CNV regions in four independent case-control series as well as an additional public in silico control group (totaling 4439 UC patients and 15,961 healthy controls) revealed three copy number variants enriched in UC patients; a 15.8 kb deletion upstream of ABCC4 and CLDN10 at13q32.1 (0.43% cases, 0.11% controls), a 119 kb duplication at 7p22.1, overlapping RNF216, ZNF815, OCM and CCZ1 (0.13% cases, 0.01% controls) and a 134 kb large duplication upstream of the KCNK9 gene at 8q24.3 (0.22% carriers among cases, 0.03% carriers among controls). The trend of association with UC was present after the P-values were corrected for combining data from different subpopulations. Break-point mapping of the deleted region suggested non-allelic homologous recombination as the mechanism underlying its formation.ConclusionOur study presents a pragmatic approach for effective rare CNV screening of SNP-array data sets and implicates the potential contribution of rare structural variants in the pathogenesis of UC.

Project description:BackgroundThe human genome displays extensive copy-number variation (CNV). Recent discoveries have shown that large segments of DNA, ranging in size from hundreds to thousands of nucleotides, are either deleted or duplicated. This CNV may encompass genes, leading to a change in phenotype, including drug response phenotypes. Gemcitabine and 1-beta-D-arabinofuranosylcytosine (AraC) are cytidine analogues used to treat a variety of cancers. Previous studies have shown that genetic variation may influence response to these drugs. In the present study, we set out to test the hypothesis that variation in copy number might contribute to variation in cytidine analogue response phenotypes.ResultsWe used a cell-based model system consisting of 197 ethnically-defined lymphoblastoid cell lines for which genome-wide SNP data were obtained using Illumina 550 and 650 K SNP arrays to study cytidine analogue cytotoxicity. 775 CNVs with allele frequencies > 1% were identified in 102 regions across the genome. 87/102 of these loci overlapped with previously identified regions of CNV. Association of CNVs with gemcitabine and AraC IC50 values identified 11 regions with permutation p-values < 0.05. Multiplex ligation-dependent probe amplification assays were performed to verify the 11 CNV regions that were associated with this phenotype; with false positive and false negative rates for the in-silico findings of 1.3% and 0.04%, respectively. We also had basal mRNA expression array data for these same 197 cell lines, which allowed us to quantify mRNA expression for 41 probesets in or near the CNV regions identified. We found that 7 of those 41 genes were highly expressed in our lymphoblastoid cell lines, and one of the seven genes (SMYD3) that was significant in the CNV association study was selected for further functional experiments. Those studies showed that knockdown of SMYD3, in pancreatic cancer cell lines increased gemcitabine and AraC resistance during cytotoxicity assay, consistent with the results of the association analysis.ConclusionsThese results suggest that CNVs may play a role in variation in cytidine analogue effect. Therefore, association studies of CNVs with drug response phenotypes in cell-based model systems, when paired with functional characterization, might help to identify CNV that contributes to variation in drug response.

Dataset Information

A genome-wide association study of copy-number variation identifies putative loci associated with osteoarthritis in Koreans.

Background

Methods

Results

Conclusion

Publications

A genome-wide association study of copy-number variation identifies putative loci associated with osteoarthritis in Koreans.

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