title: Targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Bang
authors.forename: Young-Ji
authors.initials: YJ
authors.lastname: Na
authors.forename: Kwangwoo
authors.initials: K
authors.lastname: Kim
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Joo
authors.forename: Youngho
authors.initials: Y
authors.lastname: Park
authors.forename: Jaemoon
authors.initials: J
authors.lastname: Lee
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Junghee
authors.initials: J
authors.lastname: Jung
authors.forename: Hwanseok
authors.initials: H
authors.lastname: Rhee
authors.forename: Jong-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Bok-Ghee
authors.initials: BG
authors.lastname: Han
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Ahn
authors.forename: Sungho
authors.initials: S
authors.lastname: Won
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Lee
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000208:ethnology / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D056910:Republic of Korea; D017422:Sequence Analysis, DNA / Q000379:methods*