Targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis

Arthritis Research & Therapy - Tập 16 - Trang 1-9 - 2014
So-Young Bang, Young-Ji Na1, Kwangwoo Kim1, Young Bin Joo1, Youngho Park2, Jaemoon Lee2, Sun-Young Lee3, Adnan A Ansari3, Junghee Jung4, Hwanseok Rhee4, Jong-Young Lee5, Bok-Ghee Han5, Sung-Min Ahn3,6, Sungho Won7, Hye-Soon Lee1, Sang-Cheol Bae1
1Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea
2Department of Applied Statistics, Chung-Ang University, Seoul, Republic of Korea
3Department of Oncology, Asan Medical Center, Seoul, Republic of Korea
4Bioinfomatics Center, Macrogen Inc., Seoul, Republic of Korea
5Center for Genome Science, Korea National Institute of Health, Osong Health Technology, Chungcheongbuk-do, Republic of Korea
6Department of Biomedical Informatics, Asan Medical Center, Seoul, Republic of Korea
7Public Health Science, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea

Tóm tắt

Although it has been suggested that rare coding variants could explain the substantial missing heritability, very few sequencing studies have been performed in rheumatoid arthritis (RA). We aimed to identify novel functional variants with rare to low frequency using targeted exon sequencing of RA in Korea. We analyzed targeted exon sequencing data of 398 genes selected from a multifaceted approach in Korean RA patients (n = 1,217) and controls (n = 717). We conducted a single-marker association test and a gene-based analysis of rare variants. For meta-analysis or enrichment tests, we also used ethnically matched independent samples of Korean genome-wide association studies (GWAS) (n = 4,799) or immunochip data (n = 4,722). After stringent quality control, we analyzed 10,588 variants of 398 genes from 1,934 Korean RA case controls. We identified 13 nonsynonymous variants with nominal association in single-variant association tests. In a meta-analysis, we did not find any novel variant with genome-wide significance for RA risk. Using a gene-based approach, we identified 17 genes with nominal burden signals. Among them, VSTM1 showed the greatest association with RA (P = 7.80 × 10-4). In the enrichment test using Korean GWAS, although the significant signal appeared to be driven by total genic variants, we found no evidence for enriched association of coding variants only with RA. We were unable to identify rare coding variants with large effect to explain the missing heritability for RA in the current targeted resequencing study. Our study raises skepticism about exon sequencing of targeted genes for complex diseases like RA.

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