Cell-type-resolved genetic variation shapes inflammatory bowel disease risk
Abstract
Abstract Most genetic variants associated with complex diseases lie in non-coding regions 1 , complicating efforts to identify effector genes and relevant cell types. Here we map cis -expression quantitative trait loci (eQTLs) across 2.2 million single cells using intestinal biopsies and blood from 421 individuals, including 125 with inflammatory bowel disease (IBD). Cell-type-level eQTLs were more distal to transcription start sites, enriched in enhancers, less likely to regulate the nearest gene, and more than 3.5-fold more likely to colocalize with IBD loci detected in genome-wide association studies (GWASs) than eQTLs detected at tissue-level resolution. We nominate effector genes at more than half of known IBD loci, including MAML2 , PSEN2 and ZMIZ1 in myeloid cells, implicating reduced Notch signalling in intestinal immune dysfunction. We also identify Wnt-regulated genes, including MYC , in epithelial stem and progenitor cells, suggesting that impaired renewal contributes to barrier breakdown. Our results provide a mechanistic map that links genetic risk to specific genes and cell types in IBD, and a generalized framework for interpretation of GWAS loci using single-cell eQTL mapping of disease-relevant tissues in complex diseases.
Article Details
Authors (37)
Tobi Alegbe
Bradley T. Harris
Laura Fachal
Lucia Ramirez-Navarro
Marcus Tutert
Monika Krzak
Mennatallah Ghouraba
Michelle Strickland
Matiss Ozols
Celeste E. Cohen
Saniya Khullar
Eleonora Khabirova
Nikolaos I. Panousis
David Ochoa
Noor Wana
May Xueqi Hu
Jason Skelton
Jasmin Ostermayer
Kimberly Ai Xian Cheam
D. Leland Taylor
Yong Gu
Claire Dawson
Tina Thompson
Kenneth Arestang
Nilanga Nishad
Biljana Brezina
Charry Queen Caballes
Wendy Garri
Steven Leonard
Vivek Iyer
Miles Parkes
Chris Wallace
Rebecca E. McIntyre
Cristina Cotobal Martin
Gareth-Rhys Jones
Tim Raine
Carl A. Anderson