Type of publication:
Journal article
Author(s):
Zhu, Ruifei; Zhang, Qian; Yuan, Kai; Zhang, Rui; Turvey, Alexandra K; Stevens, Christine R; Fachal, Laura; Ahmad, Tariq; Bel Kok, Klaartje; Bernstein, Charles N; Bokemeyer, Bernd; Brant, Steven R; Brooks, Johanne; *Butterworth, Jeffrey; Cho, Judy H; Clark, Katie; Cummings, Fraser; Duerr, Richard H; Ennis, Sarah; Farkkila, Martti; Faubion, William A; Foley, Stephen; Franchimont, Denis; Franke, Andre; Hancock, Laura; Hart, Ailsa; Hooper, Patricia; Irving, Peter; Jarvis, Mark; Johnston, Emma; Karlson, Elizabeth W; Kemp, Cheryl; Kennedy, Nick; Kupcinskas, Juozas; Lamb, Christopher A; Lees, Charlie; Lewis, James D; Li, Andy; Limdi, Jimmy; Loescher, Britt-Sabina; Louis, Edouard; McCauley, Jacob L; McGovern, Dermot P B; McLaughlin, John; Moayyedi, Paul; Moran, Gordon; Newberry, Rodney D; Oglesby, Arabis; Palotie, Aarno; Pekow, Joel; Perez, Kate J; Pollok, Richard; Prescott, Natalie; Raine, Tim; Ramadas, Arvind; Ramakrishnan, Subramaniam; Sabic, Ksenija; Sands, Bruce; Satsangi, Jack; Sazonovs, Aleksejs; Schreiber, Stefan; Selinger, Christian; Shedwell, Sophy; Silverberg, Mark S; Singh, Salil; Sokol, Harry; Steed, Helen; Steel, Alan; Uhlig, Holm H; Verma, Ajay; Vermeire, Severine; Weersma, Rinse K; Xavier, Ramnik J; Yu, Mingrui; Parkes, Miles; Rioux, John D; Daly, Mark J; Huang, Hailiang; Anderson, Carl A.
Citation:
MedRxiv : the Preprint Server for Health Sciences. 2026 May 20.
Abstract:
Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation1,2. Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.
DOI: 10.64898/2026.05.08.26352648
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