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. © 2013 Macmillan Publishers Limited. All rights reserved

Genetics of celiac disease

“…A recent exome sequencing study in CeD, using extended families (in a linkage analysis) and with re-sequencing of GWAS candidate genes, did not find any rare alleles in coding regions associated to the disease [27]. A similar scenario was presented by Hunt et al, who, after re-sequencing the exons of 25 candidate genes in 41,911 individuals, only identified a nearly "common" non-synonymous variant with very modest effect (rs17849502, minor allele frequency (MAF) ¼ 0.049, OR ¼ 1.35) in the NCF2 gene [26]. With hindsight, this variant was also found to be present in the CeD Immunochip study by Trynka et al, but it had been removed from further analysis by their quality control criteria [7].…”

“…Only in some exceptions have associations been seen to rare or low frequency variants (in CeD, IBD, PBC and RA), and these are often related to the number of samples analyzed and hence the study's power or methodology (e.g. the use of sequences instead of genotypes) [26]. Two examples serve to demonstrate the complex analysis leading to the discovery of rare variants.…”

Genetics of Coronary Artery Disease

“…Results of this study indicate that the proportion of heritability because of rare variants was negligible. 126 A recent study performed by crossing >2 strains of yeast in which the traits are known produced an interesting and relevant finding. They were able to account for 100% of the expected heritability through primarily common risk variants each exhibiting only minimal risk effects with gene-to-gene interactions varying from 0% to 50% of the effect.…”

Psoriasis

“…Moreover, the gene variants identified have modest-effect size and it has been hypothesized that rare variants with bigger effect may explain this "missing heritability" (Manolio et al 2009). However, a recent study, which has resequenced 25 genes from 20 GWAS-identified risk loci overlapping between six common autoimmune disease including psoriasis, has shown that rare variants at known loci have a negligible role in common immune-mediated disease susceptibility, suggesting that the missing heritability likely results from the coexistence of many common variants of weak effect (Hunt et al 2013).…”