Discovery, Fine Mapping, and Functional Characterization of Genetic Susceptibility Loci in Type 1 Diabetes
Robertson, Catherine, Biochemistry and Molecular Genetics - School of Medicine, University of Virginia
Rich, Stephen, MD-PBHS Public Health Sciences Admin, University of Virginia
Type 1 diabetes (T1D) is an autoimmune disease in which the immune system de- stroys the insulin-producing β cells of the pancreas, leading to elevated blood glucose. Twin and family studies suggest that about half of T1D risk is inherited.
In Chapter 1, I describe the genetic etiology of T1D.
Historically, Northern European populations had the highest incidence of T1D, but rates are increasing in other groups. Genetic studies of T1D in African-ancestry populations have been limited in scope and size. In Chapter 2, analyzing genotypes from 3,949 African Americans, we find genetic associations with T1D risk are broadly concordant between African- and European-ancestry groups but also demonstrate the value of population-specific genetic risk prediction.
Genetic studies conducted over the past 45 years have identified about 60 loci associated with T1D risk, but causal variants are unknown in most regions. In Chapter 3, we analyze genotypes from 16,159 T1D cases, 25,386 controls and 6,143 trio families, to identify additional T1D-associated regions and, in 52 regions, define “credible sets” of variants most likely to be causal for T1D.
The vast majority of T1D credible variants are in non-coding regions of the genome, which obscures the causal genes and mechanisms underlying their association. In Chapter 4, we identify causal cell types, variants, and genes for T1D using chromatin accessibility profiling. We demonstrate strong enrichment of T1D credible variants in open chromatin from lymphocytes, and find five regions where T1D credible variants influence chromatin accessibility in CD4+ T cells.
These analyses expand our understanding of the genetic basis of T1D. In Chapter 5, I discuss how continued work to understand genetic risk for T1D in diverse ancestry and later-onset populations will pave the way for effective precision medicine in T1D. High throughput approaches to test variant function in diverse cell contexts will accelerate the effort to definitively link causal genes to T1D etiology, providing novel therapeutic targets and guiding application of therapies.
PHD (Doctor of Philosophy)
type 1 diabetes, genetics