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01.12.2015 | Research article | Ausgabe 1/2015 Open Access

BMC Musculoskeletal Disorders 1/2015

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

BMC Musculoskeletal Disorders > Ausgabe 1/2015
Sanghoon Moon, Bhumsuk Keam, Mi Yeong Hwang, Young Lee, Suyeon Park, Ji Hee Oh, Yeon-Jung Kim, Heun-Sik Lee, Nam Hee Kim, Young Jin Kim, Dong-Hyun Kim, Bok-Ghee Han, Bong-Jo Kim, Juyoung Lee
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12891-015-0531-4) contains supplementary material, which is available to authorized users.
Sanghoon Moon and Bhumsuk Keam contributed equally to this work.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

SM: manuscript writing, conception and design, data analysis. BK: manuscript writing, analysis and interpretation of data. MYH: data analysis, data management. YL: data analysis. SP: data analysis. JHO: validation experiment. YJK: validation experiment. HSL: manuscript writing of a part of discussion. NHK: data manual curation, data analysis. YJK: data manual curation, data analysis. DHK: data collection, result interpretation. BGH: comments for project design, final approval of the version to be published. BJK: conception and design, project management. JL: data collection, conception and design, project management. All authors have read and approved the final manuscript for publication.



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.


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.


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.


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.
Additional file 1: Overall scheme of this study. A genome-wide association study of CNVs was conducted using 371 of OA cases and 467 controls. Consequently, six candidate CNV regions were selected.
Additional file 2: Result of CNVtools with estimated genotypes and Log2 ratio information. We used LDF value among three different genotype information such as raw, PCA, and LDF. PCA: Principal components analysis, LDF: linear discrimination function.
Additional file 3: CNV classes. For the CNV genotyping stage, we assigned individuals to each CNV cluster according to the log2 ratio between test sample and reference sample. (A) Single-class CNVs, in which all individuals of the CNV region belonged to one cluster, were excluded from further study. (B, C) Only multi-class CNVs that consisted of two (B) or three (C) clusters were used for the association analysis.
Additional file 4: Genotypes and validation results of the CNV region onTNKS. (A) The Histogram represents the signal intensity of log2 ratio for OA cases (left) and controls (right). CNV genotypes of this region were clearly separated into three groups (homozygous deletion, heterozygous deletion and normal). The colored lines (black, green and cyan) show the posterior probability for each of the three copy number classes (homozygous deletion, heterozygous deletion and normal copy). (B) Quantitative PCR results showed that the validated genotype was highly concordant with estimated CNV genotype. The copy number state of cases (left) and control samples (right). Higher bar, lower bar and no bar in each figure represent a normal number of copies, heterozygous deletion, and homozygous deletion, respectively. The Blue bar means copy number state of the NA10851 sample, which was used as the reference sample.
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