Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7

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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.

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Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Katrina M de Lange, Loukas Moutsianas, James Lee … (2017)

Genetic association studies have identified 215 risk loci for inflammatory bowel disease 1–8, which have revealed fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new loci, three of which contain integrin genes that encode proteins in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at previously implicated loci (ITGAL, ICAM1). In all four cases, the expression increasing allele also increases disease risk. We also identified likely causal missense variants in the primary immune deficiency gene PLCG2 and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new common variant associations continue to identify genes relevant to therapeutic target identification and prioritization.

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Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

David Ellinghaus, Luke Jostins, Sarah L Spain … (2016)

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European-ancestry we identified 244 independent multi-disease signals including 27 novel genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multi-disease signals with expression data sets from human, rat and mouse, and epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases that is genetically identical to another disease, possibly due to diagnostic misclassification, molecular subtypes, or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

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Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.

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A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 x 10(-4), combined P = 2.1 x 10(-10)) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.