title: Rare, low-frequency, and common variants in the protein-coding sequence of biological candidate genes from GWASs contribute to risk of rheumatoid arthritis.
abstract: The extent to which variants in the protein-coding sequence of genes contribute to risk of rheumatoid arthritis (RA) is unknown. In this study, we addressed this issue by deep exon sequencing and large-scale genotyping of 25 biological candidate genes located within RA risk loci discovered by genome-wide association studies (GWASs). First, we assessed the contribution of rare coding variants in the 25 genes to the risk of RA in a pooled sequencing study of 500 RA cases and 650 controls of European ancestry. We observed an accumulation of rare nonsynonymous variants exclusive to RA cases in IL2RA and IL2RB (burden test: p = 0.007 and p = 0.018, respectively). Next, we assessed the aggregate contribution of low-frequency and common coding variants to the risk of RA by dense genotyping of the 25 gene loci in 10,609 RA cases and 35,605 controls. We observed a strong enrichment of coding variants with a nominal signal of association with RA (p < 0.05) after adjusting for the best signal of association at the loci (p(enrichment) = 6.4 × 10(-4)). For one locus containing CD2, we found that a missense variant, rs699738 (c.798C>A [p.His266Gln]), and a noncoding variant, rs624988, reside on distinct haplotypes and independently contribute to the risk of RA (p = 4.6 × 10(-6)). Overall, our results indicate that variants (distributed across the allele-frequency spectrum) within the protein-coding portion of a subset of biological candidate genes identified by GWASs contribute to the risk of RA. Further, we have demonstrated that very large sample sizes will be required for comprehensively identifying the independent alleles contributing to the missing heritability of RA.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Diogo
authors.forename: Fina
authors.initials: F
authors.lastname: Kurreeman
authors.forename: Eli A
authors.initials: EA
authors.lastname: Stahl
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Liao
authors.forename: Namrata
authors.initials: N
authors.lastname: Gupta
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Greenberg
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Rivas
authors.forename: Brendan
authors.initials: B
authors.lastname: Hickey
authors.forename: Jason
authors.initials: J
authors.lastname: Flannick
authors.forename: Brian
authors.initials: B
authors.lastname: Thomson
authors.forename: Candace
authors.initials: C
authors.lastname: Guiducci
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.forename: Ivan
authors.initials: I
authors.lastname: Adzhubey
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Joel M
authors.initials: JM
authors.lastname: Kremer
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Shamil
authors.initials: S
authors.lastname: Sunyaev
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.forename: John
authors.initials: J
authors.lastname: Bowes
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D005091:Exons; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors