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From Genome-Wide SNPs to Neuroimmune Crosstalk: Mapping the Genetic Landscape of IBD and Its Brain Overlap
by
, ,
Utkarsh Tripathi
1
,
Yam Stern
1,
Inbal Dagan
1,
Ritu Nayak
1,
Eva Romanovsky
1,
Eran Zittan
2 and
Shani Stern
1,* 1
Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 3498838 , Israel
2
The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel
*
Author to whom correspondence should be addressed.
Biology 2025, 14(10), 1433; https://doi.org/10.3390/biology14101433
Submission received: 5 August 2025
/
Revised: 9 October 2025
/
Accepted: 13 October 2025
/
Published: 17 October 2025
Simple Summary
Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is a long-term illness that causes inflammation in the gut. Scientists have found that IBD is not only a disease of the intestines but can also affect the brain, leading to problems such as depression, anxiety, and other neurological conditions. In this study, we examined genetic data from large international studies to identify genes that increase the risk of IBD. We then explored how these genes are expressed in both the gut and the brain. Our results showed that many of the same genes active in IBD are also active in specific brain regions and are involved in pathways that regulate immunity, stress response, and nerve function. This suggests that the genetic background of IBD may also influence brain health. By highlighting these shared pathways, our findings provide insights into why people with IBD are more likely to experience neurological or psychiatric problems. This knowledge could help guide new treatments, not only for IBD but also for related brain conditions and may eventually improve patient care by addressing the disease in a more holistic way.
Abstract
Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), arises from complex genetic and environmental interactions. Here, we integrate genome-wide association study (GWAS) meta-analyses with tissue-specific expression data from GTEx to map the polygenic architecture of IBD and its systemic implications. We identified 69 genome-wide significant single-nucleotide polymorphisms (SNPs) across 26 genes shared by CD and UC, revealing an almost equal partition of subtype-specific (50.7%) and shared (49.3%) risk variants. IL23R exhibited the highest allelic heterogeneity—three UC-specific, one CD-specific, and three shared SNPs—while ATG16L1′s four CD-specific variants underscored autophagy’s pivotal role in CD. Chromosomal mapping revealed distinct regulatory hotspots: UC-only loci on chromosomes 1 and 6, CD-only loci on chromosomes 10 and 16, and shared loci on chromosomes 7 and 19. Pathway enrichment emphasized IL-23/IL-17, Th17 differentiation, NF-κB, and JAK–STAT signaling as central to IBD pathogenesis. GTEx analyses showed uniformly high expression of IBD genes in gastrointestinal tissues, but pronounced heterogeneity across brain regions, including the cerebellum, frontal cortex, and hippocampus. This neuro-expression, together with enrichment of neurotrophin and neurodegeneration pathways and a nearly two-fold gene overlap with autism spectrum disorder, schizophrenia, and depression (FDR < 0.05), provides integrative evidence for gut–brain axis involvement in IBD. These findings consolidate prior work while extending perspectives on systemic disease implications. This study consolidates and systematizes dispersed genetic and transcriptomic findings into a unified reference framework. Our results highlight recurrent immune-regulatory and neuro-inflammatory pathways shared between gut and brain, offering a resource to guide future mechanistic, clinical, and translational investigations in IBD and related disorders.
