In a multi-ancestry meta-analysis of genome-wide association studies encompassing 63,415 cases across European and East Asian populations, researchers have identified 60 previously unreported susceptibility loci associated with inflammatory bowel disease.

To connect these genetic associations to regulatory mechanisms, the investigators integrated multi-ancestry transcriptome-wide association studies, cell type-specific transcriptome-wide analyses, alternative splicing, and alternative polyadenylation assessments. These evaluations utilized RNA-sequencing data obtained from normal colon tissues representing 707 European individuals and 364 East Asian individuals.

Through this multi-omic framework, the research team identified 441 candidate risk genes, including 324 genes not previously implicated by genome-wide or transcriptome-wide association studies. Statistical support from colocalization or summary-data-based Mendelian randomization analyses further reinforced 291 of these candidate genes.

The candidate risk genes converge on biological pathways central to inflammatory bowel disease pathogenesis, including immune regulation, with more than half showing transcriptional dysregulation supported by single-cell and spatial omics analyses. In addition, the analysis pinpointed 44 druggable genes linked to 221 approved drugs or Phase II/III clinical-stage compounds, offering insights for precision medicine research.

The primary analytical objective centered on advancing the genetic understanding of inflammatory bowel disease by capturing genetic variation across ancestrally diverse populations. By conducting meta-analyses of genome-wide association studies across cohorts of European and East Asian ancestry comprising 63,415 cases, the investigative team expanded the known genomic landscape of the condition. This multi-ancestry design enabled the identification of 60 susceptibility loci that were previously unreported, demonstrating the utility of examining diverse ancestral groups to uncover genetic risk signals that remained undetected in single-ancestry evaluations.

To investigate how these genetic variants alter regulatory mechanisms in relevant anatomical sites, the researchers deployed an extensive multi-omic analysis centered on normal colon tissues. They integrated multi-ancestry transcriptome-wide association studies, cell type-specific transcriptome-wide association studies, alternative splicing assessments, and alternative polyadenylation profiling. These complementary transcriptomic evaluations were conducted using RNA-sequencing data collected from normal colon tissue samples representing 707 European individuals and 364 East Asian individuals, providing direct molecular evidence from the tissue environment affected by the disease.

From this integrated pipeline, the researchers pinpointed 441 candidate risk genes, representing a substantial expansion of the disease’s known biology. Notably, 324 of these candidate genes had not been implicated by earlier genome-wide or transcriptome-wide association studies. The investigators applied additional analytical tests to validate these discoveries, finding that 291 candidate genes were further supported by colocalization analyses or summary-data-based Mendelian randomization. High-resolution single-cell and spatial omics analyses further established that more than half of the candidate risk genes exhibited transcriptional dysregulation, converging functionally on pathways central to disease pathogenesis, including immune regulation.

The study also evaluated potential therapeutic implications by screening the identified risk candidates for pharmacological relevance. This translational analysis uncovered 44 druggable genes that are directly linked to 221 compounds, encompassing both regulatory-approved medications and therapies currently undergoing Phase II or Phase III clinical trials. The researchers emphasized that these drug-gene connections provide crucial insights to inform future precision medicine investigations, while clarifying the underlying genetic architecture of inflammatory bowel disease.

Subject of Research: Multi-ancestry genetic and transcriptomic identification of inflammatory bowel disease risk loci and candidate genes

Article Title: Multi-ancestry genome-wide and transcriptome-wide association analyses identify new risk loci and genes for inflammatory bowel disease

Article References: Lyu, L., Li, Q., Li, C., Dawwas, G. K., Chen, Y., Tao, R., Liu, Q., Wen, W., Shu, X.-O., Washington, K., Schwartz, D. A., Zheng, W., Yin, Z., Lau, K. S., & Guo, X. (2026). Multi-ancestry genome-wide and transcriptome-wide association analyses identify new risk loci and genes for inflammatory bowel disease. Nature Communications. https://doi.org/10.1038/s41467-026-79302-1

Image Credits: AI Generated

DOI: 10.1038/s41467-026-79302-1

Keywords: inflammatory bowel disease, genetics, genome-wide association studies, transcriptome-wide association studies, multi-ancestry analysis, risk loci, precision medicine, gene regulation, Multi-ancestry, genome-wide, transcriptome-wide, association