title: Negligible impact of rare autoimmune-locus coding-region variants on missing heritability.
abstract: Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute. To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect.
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Hunt
authors.forename: Vanisha
authors.initials: V
authors.lastname: Mistry
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Bockett
authors.forename: Tariq
authors.initials: T
authors.lastname: Ahmad
authors.forename: Maria
authors.initials: M
authors.lastname: Ban
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Barker
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barrett
authors.forename: Hannah
authors.initials: H
authors.lastname: Blackburn
authors.forename: Oliver
authors.initials: O
authors.lastname: Brand
authors.forename: Oliver
authors.initials: O
authors.lastname: Burren
authors.forename: Francesca
authors.initials: F
authors.lastname: Capon
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.forename: Stephen C L
authors.initials: SC
authors.lastname: Gough
authors.forename: Luke
authors.initials: L
authors.lastname: Jostins
authors.forename: Yong
authors.initials: Y
authors.lastname: Kong
authors.forename: James C
authors.initials: JC
authors.lastname: Lee
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.forename: John C
authors.initials: JC
authors.lastname: Mansfield
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mein
authors.forename: Muddassar
authors.initials: M
authors.lastname: Mirza
authors.forename: Sarah
authors.initials: S
authors.lastname: Nutland
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.forename: Efterpi
authors.initials: E
authors.lastname: Papouli
authors.forename: Miles
authors.initials: M
authors.lastname: Parkes
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: Steven
authors.initials: S
authors.lastname: Sawcer
authors.forename: Jack
authors.initials: J
authors.lastname: Satsangi
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Simmonds
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.forename: Eva
authors.initials: E
authors.lastname: Wozniak
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics*; D010641:Phenotype; D018401:Sample Size; D006113:United Kingdom; D044465:White People / Q000235:genetics