Novel approaches to dissect the genetic susceptibilities to celiac disease

Abstract Celiac disease (CeD) affects approximately 1% of the U.S. population. It is associated with several co- morbidities, including osteoporosis, type 1 diabetes (T1DM), anemia, reduced quality of life, and increased cancer risk. Currently, there is no approved drug to treat CeD, and the primary management strategy—strict adherence to a gluten-free diet—is not always fully effective. Human genetics play a critical role in CeD, as the presence of HLA-DQ2 or DQ8 is necessary for disease development, but not sufficient on its own to cause it. Our aim is to identify additional genetic factors that influence the clinical penetrance of HLA-DQ2 or DQ8. We recruited 51 families with multiple affected individuals and conducted exome sequencing to create a familial CeD cohort. In addition, we utilized whole genome sequencing data from 1,930 CeD patients enrolled in the All of Us research program (AoU-CeD cohort). Our analysis of genomic data from these two cohorts has led to important discoveries and unexpected insights. In this R03 grant, we propose to further explore the genetic risks for CeD using three innovative approaches based on next-generation sequencing data. Our first aim is to identify functional variants in linkage disequilibrium with the AH8.1 (A1:B8:C7:DR3:DQ2) haplotype, which includes the high-risk HLA-DQ2.5 allele. The second aim focuses on gene burden testing and pathway analysis to identify rare variants and evaluate their impacts on CeD. The third aim seeks to identify genetic risk factors for CeD in patients with admixed African and American ancestry. Through this research, we hope to uncover novel genetic factors that can enhance risk stratification and identify potential therapeutic targets for patients from diverse ethnic and genetic backgrounds. These findings could significantly improve genetic diagnosis and guide future therapeutic strategies for CeD.