Exploring the genetic architecture of inflammatory bowel disease by whole genome sequencing identifies association atADCY7

Abstract

To further resolve the genetic architecture of the inflammatory bowel diseases, ulcerative colitis and Crohn's disease, we sequenced the whole genomes of 4,280 patients at low coverage, and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing GWAS cohorts, and tested for association at ~12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants, and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn's disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve our understanding of the biology of complex diseases.

Review article: the gut microbiome in inflammatory bowel disease—avenues for microbial management

“…Genome‐wide association studies (GWAS) have now identified 235 inflammatory bowel disease (IBD)‐associated susceptibility loci, substantially expanding our understanding of the biology underlying these diseases . Early genetic studies focused on searching protein coding sequences, although it is now recognised that coding variation explains only ~20% of genetic variation associated with IBD GWAS loci .…”

Genome‐wide association studies in Crohn's disease: Past, present and future

“…Fourth, it has been proposed that rare variants – which are not included on GWAS chips but which could have much larger effect sizes – might account for some of the missing heritability. However, several studies have now been performed to attempt to identify rare disease‐associated variants, but without much success – mirroring the situation in other diseases . Fifth, because most GWAS SNPs are proxies for the true causal variant, estimates of variance based on these are likely to underestimate the true attributable risk at each locus.…”

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

“…Moreover, there is increasing evidence that genome sequencing might be more powerful at detecting exonic variants than whole exome sequencing . An example of applying low coverage exome sequencing to find an associative gene is the identification of ADC7Y in a study of 4280 patients at low coverage.…”