Integrating Genetics With Epidemiological Measurements Identifies Burden QTLs of Inflammatory Bowel Disease across 20 Countries.

It remains unclear whether the observed heterogeneity in the burden of inflammatory bowel disease (IBD) across countries is associated with differences in population genetic structure. To address this problem, we performed a burden quantitative trait locus (bQTL) analysis, integrating epidemiological data (1990-2021) from the Global Burden of Disease (GBD) study with genotypes of 2 621 978 SNPs from 2414 unrelated individuals in the 1000 Genomes Project across 20 matched countries. We identified 1074 bQTLs of IBD, of which 384 were significantly associated with both the age-standardized prevalence rate and age-standardized incidence rate. rs7633471 (chr3:30698616:C>A) showed the strongest effect: each increase in centi-allele frequency (CAF) of the allele C was associated with a 10.00 decrease in age-standardized prevalence rate and a 1.02 decrease in age-standardized incidence rate. Pathway analysis revealed that bQTLs were primarily enriched in synaptic membrane, voltage-gated potassium channel complex, and potassium channel complex. Through fine-mapping, we further identified 800 putative causal variants for IBD, with significant findings located within genes related to the immune system (IGSF21 and CSMD2), inflammatory response (SMPDL3B and AOAH), and intestinal cancers (FHIT and CSMD2). Our study provides the first comprehensive characterization of the genetic architecture underlying the global burden of IBD.