Document Type


Publication Date



JGM, Adolescent, Adult, Aged, Aged, 80 and over, Animals, Blood Glucose, Cell Line, Tumor, Cohort Studies, Diabetes Mellitus, Type 2, Diacylglycerol Kinase, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Islets of Langerhans, Male, Mice, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, RNA-Seq, Sequence Analysis, DNA, Transcription Factor 7-Like 2 Protein, Young Adult

JAX Source

Nat ommun 2020 Sep 30; 11(1):4912





Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.


This article is licensed under a Creative Commons Attribution 4.0 International License.