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Advisory Committee Chair

Stanley L Bridges

Advisory Committee Members

Robinna G Lorenz

Hemant K Tiwari

Robert P Kimberly

Sean Davis

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Rheumatoid arthritis (RA) is a complex disease having numerous genetic and environmental risk factors the interplay of which produces RA pathobiology. While the sheer number of genetic and environmental risk factors complicates understanding of disease biology, understanding has progressed far enough for insight into the most likely mechanisms for the development of the disease. Modern studies of the genetics of RA are massively parallel, enabling researchers to systematically interrogate variants throughout the human genome for associations in genome-wide association studies or GWAS. Such studies have been carried out in European and Asian cohorts many times, and the most recent RA meta-analyses includes tens of thousands of genotypes from these populations. By contrast, there is a paucity of genotyping data available in individuals of African ancestry with RA. In the studies that follow, we attempt to address this disparity by presenting the largest genetic studies in African-Americans to date. Following these association studies, we employ fine-mapping methods, which operate on association results and output a (short) list of candidate pathogenic. Recent studies have become increasingly sophisticated in their approaches to this. One such approach is trans-ethnic fine-mapping, which uses differences in the association pattern and LD between variants in the same risk locus across multiple global populations. By examining these together, fine-mapping algorithms can estimate which variants are the most likely to be the pathogenic variants. In the present studies, we carry out fine-mapping studies using aggregated data that draws on >100,000 RA patients and controls from 3 global ancestries. Thus, our studies had 3 chief aims. First, we aimed to discover novel associations with RA that have not been found before in other ethnicities. Second, we endeavored to validate in African-Americans known associations identified in genetic studies of RA in Asians and Europeans with RA. Last, we employed trans-ethnic fine-mapping algorithms to isolate candidate causal variants in the loci we identified. Pursuant to the first aim, we find 3 novel associations with RA in the CSMD3, GPC5, and RBFOX1 loci that appear to be unique to individuals of African ancestry. Second, we replicate 28 genetic risk loci discovered in other populations, and present evidence that 4 such loci are unlikely to replicate. Last, we identify several new candidate pathogenic variants, including several that may have relevance for precision medicine. The findings in these studies have far-ranging implications for the design of future genetic studies, in particular for those that hope to cost-effectively identify functional variants that produce RA, which is necessary before mechanistic studies of how genetic variants can produce disease risk can begin. Therefore, the present study can serve as a basis for future studies into the genetics of RA in global populations. Keywords: Rheumatoid Arthritis, Genetics, GWAS, meta-analysis, trans-ethnic, fine- mapping, complex disease, post-GWAS, African-American

Table_S2_TEMA.xlsx (67 kB)
Supplemental Data - Table S2 TEMA

Table_S3_TEFM.xlsx (94 kB)
Supplemental Data - Table S3 TEFM

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