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
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.
Viñuela, Ana; Varshney, Arushi; van de Bunt, Martijn; Prasad, Rashmi B; Asplund, Olof; Bennett, Amanda; Boehnke, Michael; Brown, Andrew A; Erdos, Michael R; Fadista, João; Hansson, Ola; Hatem, Gad; Howald, Cédric; Iyengar, Apoorva K; Johnson, Paul; Krus, Ulrika; MacDonald, Patrick E; Mahajan, Anubha; Manning Fox, Jocelyn E; Narisu, Narisu; Nylander, Vibe; Orchard, Peter; Oskolkov, Nikolay; Panousis, Nikolaos I; Payne, Anthony; Stitzel, Michael L.; Vadlamudi, Swarooparani; Welch, Ryan; Collins, Francis S; Mohlke, Karen L; Gloyn, Anna L; Scott, Laura J; Dermitzakis, Emmanouil T; Groop, Leif; Parker, Stephen C J; and McCarthy, Mark I, "Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D." (2020). Faculty Research 2020. 208.