Type 2 Diabetes–Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets
Abstract
Type 2 diabetes (T2D) is a complex disorder in which both genetic and environmental risk factors contribute to islet dysfunction and failure. Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs), most of which are noncoding, in >200 loci to islet dysfunction and T2D. Identification of the putative causal variants and their target genes and whether they lead to gain or loss of function remains challenging. Here, we profiled chromatin accessibility in pancreatic islet samples from 19 genotyped individuals and identified 2,949 SNPs associated with in vivo cis-regulatory element use (i.e., chromatin accessibility quantitative trait loci [caQTL]). Among the caQTLs tested (n = 13) using luciferase reporter assays in MIN6 β-cells, more than half exhibited effects on enhancer activity that were consistent with in vivo chromatin accessibility changes. Importantly, islet caQTL analysis nominated putative causal SNPs in 13 T2D-associated GWAS loci, linking 7 and 6 T2D risk alleles, respectively, to gain or loss of in vivo chromatin accessibility. By investigating the effect of genetic variants on chromatin accessibility in islets, this study is an important step forward in translating T2D-associated GWAS SNP into functional molecular consequences.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 04, 2018
- Source ID
- 10.2337/db18-0393
Entities
People
- Ahrim Youn
- Alexandria Jillette
- Duygu Ucar
- Eladio J. Marquez
- Michael L Stitzel
- Nathan Lawlor
- Romy Kursawe
- Shubham Khetan
Organizations
- American Diabetes Association
- Congressionally Directed Medical Research Programs
- Jackson Laboratory
- National Institute of Diabetes and Digestive and Kidney Diseases
- University of Connecticut