Pathway specific polygenic risk scores identify pathways and patient clusters associated with inflammatory bowel disease risk, severity and treatment response

Crohns disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) with a strong genetic component [1,2]. Genome-wide association studies (GWAS) have successfully identified over 240 genetic loci that are statistically associated with risk of developing IBD, and these associations provide valuable insights into disease pathobiology. Building on GWAS findings, conventional polygenic risk scores (cPRS) aim to quantify the aggregated disease risk based on DNA variation, and these scores can identify individuals at high risk. While stratifying individuals based on cPRS has the potential to inform clinical care, the development of novel therapeutics requires deep insight into how aggregated genetic risk leads to disruption of specific biological pathways. Here, we developed a pathway-specific PRS (pPRS) methodology to assess IBD common variant genetic risk burden across 31 manually curated pathways. We first prioritized 206 genes based on comprehensive fine-mapping and eQTL colocalization analyses of genome-wide significant IBD GWAS loci and 58 highly penetrant genes based on their involvement in early onset IBD or autoimmunity-related colitis. These 264 genes were assigned to at least one of the 31 pathways based on Gene Ontology annotations and manual curation. Finally, we integrated these inputs into a novel pPRS model and performed an extensive investigation of IBD disease risk, severity, complications, and anti-TNF treatment response by applying our pPRS approach to three complementary datasets encompassing IBD cases and controls. Our analysis identified multiple promising pathways that can inform drug target discovery and provides a patient stratification method that offers insights into the biology of treatment response.