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

So-Young Bang, Young-Ji Na, Kwangwoo Kim, Young Bin Joo, Youngho Park, Jaemoon Lee, Sun-Young Lee, Adnan A Ansari, Junghee Jung, Hwanseok Rhee, Jong-Young Lee, Bok-Ghee Han, Sung-Min Ahn, Sungho Won, Hye-Soon Lee, Sang-Cheol Bae

IntroductionAlthough 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.MethodsWe 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 test, we also used ethnically matched independent samples of Korean genome-wide association studies (GWAS) (n¿=¿4,799) or immunochip data (n¿=¿4,722).ResultsAfter stringent quality control, we analyzed 10,588 variants of 398 genes from 1,934 Korean RA case-controls. We identified 13 non-synonymous 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.ConclusionsWe 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.