OP001 Whole genome sequencing and imputation in inflammatory bowel disease identifies 26 novel loci and offers therapeutically-relevant mechanistic insights
Moutsianas L.*1, De Lange K.1, Luo Y.1,2,3, Lee J.4, Jostins L.5, Lamb C.6, Kennedy N.7, Mansfield J.8, Parkes M.4, Barrett J.1, Anderson C.1
1Wellcome Trust Sanger Institute, Human Genetics, Hinxton, Cambridge, United Kingdom 2Broad Institute of Harvard and MIT, Program in Medical and Population Genetics, Cambridge, United States 3Harvard Medical School, Division of Genetics and Rheumatology, Boston, United States 4Addenbrooke's Hospital, Inflammatory Bowel Disease Research Group, Cambridge, United Kingdom 5Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom 6Newcastle University, Newcastle upon Tyne, United Kingdom 7University of Exeter, Precision Medicine Exeter, Exeter, United Kingdom 8University of Newcastle, Human Genetics, Newcastle upon Tyne, United Kingdom
Most of the 215 risk loci associated with inflammatory bowel diseases (IBD) to date were discovered by genotyping arrays and are driven by common variants. Such assays, however, do not adequately capture lower frequency variation. Thus, the role of these variants in IBD pathogenesis is unclear.
To comprehensively interrogate the role of lower frequency variation, we whole-genome sequenced (WGS) 4280 IBD patients and compared them to 3652 population controls. To increase power to detect association, we imputed into new and existing GWAS cohorts totalling over 35000 individuals, using a reference panel augmented with our sequence data. Finally, we combined our data with publicly available summary statistics and conducted meta-analyses in ∼60,000 individuals.
We conducted a large, multi-faceted study to explore the genetic architecture of IBD across the entire allele frequency spectrum. Our results highlight the continued value of GWAS and their potentially pivotal role in understanding aspects of disease biology through the integration of genomic and functional datasets in specific cells and contexts. We found minimal evidence for strong effects from low frequency variants, despite good power, while the effects of rare variants will require larger sample sizes to be more thoroughly investigated.