Characterizing the Genetic Landscape of Inflammatory Bowel Disease Across Populations Público

Pelia, Ranjit (Summer 2025)

Permanent URL: https://etd.library.emory.edu/concern/etds/4x51hk48x?locale=es
Published

Abstract

Background: Inflammatory bowel disease (IBD) is a complex, polygenic, and multi-faceted disease comprised of two main forms, Crohns disease (CD) and ulcerative colitis (UC). Despite the similar prevalence of IBD among Americans, there are stark differences in severity amongst individuals with European versus African, admixed, ancestries. Over 300 susceptibility loci have been identified in IBD. Detecting statistically significant genetic variants across populations will aid clinicians by optimizing for IBD-subset and patient heterogeneity.

Objective: The goal of this proposal is to characterize novel and assess known IBD-risk associated loci using one of the most diverse genomic datasets to date. Our combined- blended-Genome-Exome (cBGE) approach will elucidate novel IBD related associations, improve genetic risk predictions across all populations, and provide mechanistic insights. Our overarching objective is to characterize IBD-risk associated loci across diverse populations using combined-Blended 

Genome Exome sequencing (cBGE).

Method: Peripheral blood samples derived from IBD patients and controls was sequenced using cBGE and combined with Whole Genome Sequencing to generate a predominantly African 

American population dataset. Variants were identified following best practices using GATK, annotated with Bystro, and quality control analyses using PLINK2. Common and rare variant 

association testing, Polygenic Risk Scores and pathway analyses was performed using IBD, CD, and UC specific variants across populations. Results were compared with previously discovered IBD associated loci and novel findings were reported. 

Results: A merged, n=1794 cBGE and n=3608 WGS, dataset was harmonized leading to n=5374 after harmonization. Over 6.5 million variants were observed in IBD patients comprised of SNPs and INDELs. Genomic inflation, l in IBD, CD, and UC was l=1.014, l=1.012, and l=1.014. We observed PTGER4, CARD9, and IL23R common and rare variants across disease subtypes.

Polygenic risk scores were more similar across IBD and CD compared to UC. Pathway analysis highlight cell adhesion in IBD, chromatin remodeling in CD, and T-cell regulation in UC.

Conclusion: The duality of cBGE with WGS increased our power from previous investigations leading to validation of known IBD-associated loci. No significant novel variants were observed showing the limitations of cBGE. Here, we provide the largest known African American population genetic dataset in IBD. 

Table of Contents

1.     Introduction:

                        I.         Inflammatory Bowel Disease…………………………………………pages 8-10

                      II.         Genetics of Inflammatory Bowel Disease…………………………….pages 11

                    III.         Population Genetics and Inflammatory Bowel Disease………………pages 11-12

2.     Methods:

                        I.         Inflammatory Bowel Disease Genetics Consortium………………….pages 13

                      II.         DNA Sample Collection, Extraction, Clinical Phenotypes, and Sequencing……………………………………………………………pages 13

                    III.         Harmonization and First-Pass Quality Control……………………….pages 14

                   IV.         Common Variant Association Analysis………………………………pages 15

                     V.         Rare Variant Association Analysis……………………...……………pages 15

                   VI.         Polygenic Risk Scores……………………………………………...…pages 15

                 VII.         Pathway Analysis…………………………………………………..…pages 15

3.     Results:

                        I.         Power Calculation and Summary Statistics of Clinical Phenotypes.….pages 16

                      II.         Quality Control of Post-Alignment Variant-Called-Files……….…….pages 16

                    III.         Common Variant Association Analysis……………………………….pages 17

                   IV.         Rare Variant Association Analysis…………………………….……...pages 17-18

                     V.         Polygenic Risk Scores……………………………………….………...pages 18

                   VI.         Pathway Analysis…….......…………………………….………….......pages 18

4.     Discussion…….......………………………………………...............................pages 19

5.     Figures…….......……………………………………….....................................pages 20-28

6.     Tables…….......………………………………………......................................pages 29-35 

7.     Bibliography…….......………………………………………............................pages 36-39

About this Master's Thesis

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
School
Department
Subfield / Discipline
Degree
Submission
Language
  • English
Research Field
Palabra Clave
Committee Chair / Thesis Advisor
Última modificación

Primary PDF

Thumbnail Title Date Uploaded Actions
Characterizing the Genetic Landscape of Inflammatory Bowel Disease Across Populations () 2025-07-31 12:40:21 -0400

Supplemental Files

Thumbnail Title Date Uploaded Actions
Top 1000 Variants in Inflammatory Bowel Disease (Using n=2050 controls and n=3324 Inflammatory Bowel Disease patients, the top 1000 variants by p value are shown. The variants are annotated using Bystro, CADD, and GnomAD.) 2025-07-31 12:40:28 -0400
Top 1000 Variants in Crohns Disease (Using n=2050 controls and n=2361, the top 1000 variants by p-value are shown. The variants are annotated using Bystro, CADD, and GnomAD.) 2025-07-31 12:40:36 -0400
Top 1000 Variants in Ulcerative Colitis (Using n=2050 controls and n=963, the top 1000 variants by p-value are shown. The variants are annotated using Bystro, CADD, and GnomAD.) 2025-07-31 12:40:46 -0400