1. Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D
- Author
-
Peter Orchard, Jocelyn E. Manning Fox, Anthony Payne, Karen L. Mohlke, Laura J. Scott, Nikolay Oskolkov, Anubha Mahajan, Andrew A. Brown, Apoorva K Iyengar, Paul Johnson, Ola Hansson, Patrick E. MacDonald, Michael L. Stitzel, Ulrika Krus, Ana Viñuela, Cédric Howald, Narisu Narisu, Gad Hatem, Anna L. Gloyn, Nikolaos I Panousis, Michael R. Erdos, Leif Groop, Vibe Nylander, Olof Asplund, João Fadista, Francis S. Collins, Emmanouil T. Dermitzakis, Amanda J. Bennett, Swarooparani Vadlamudi, Arushi Varshney, Rashmi B. Prasad, Stephen C. J. Parker, Mark I. McCarthy, Michael Boehnke, Martijn van de Bunt, Ryan P. Welch, Brown, Andrew Anand, Howald, Cédric, Panousis, Nikolaos, Dermitzakis, Emmanouil, Institute for Molecular Medicine Finland, University of Helsinki, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, and University Management
- Subjects
0301 basic medicine ,Blood Glucose ,Male ,endocrine system diseases ,General Physics and Astronomy ,Genome-wide association study ,Cohort Studies ,Mice ,0302 clinical medicine ,ddc:590 ,Transcriptional regulation ,80 and over ,ddc:576.5 ,RNA-Seq ,lcsh:Science ,Genetics ,Regulation of gene expression ,Aged, 80 and over ,ARCHITECTURE ,Multidisciplinary ,geography.geographical_feature_category ,Tumor ,1184 Genetics, developmental biology, physiology ,Type 2 diabetes ,Single Nucleotide ,Middle Aged ,Islet ,OPEN CHROMATIN ,Transcription Factor 7-Like 2 Protein/genetics/metabolism ,medicine.anatomical_structure ,Enhancer Elements, Genetic ,Regulatory sequence ,Blood Glucose/genetics/metabolism ,Female ,Islets of Langerhans/metabolism ,MESSENGER-RNA ,Transcription Factor 7-Like 2 Protein ,Sequence Analysis ,Type 2/blood/genetics ,Adult ,BETA-CELL LINE ,Diacylglycerol Kinase ,endocrine system ,Adolescent ,Enhancer Elements ,Science ,Quantitative Trait Loci ,Biology ,INSULIN-SECRETION ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cell Line ,03 medical and health sciences ,Islets of Langerhans ,Young Adult ,Genetic ,Cell Line, Tumor ,medicine ,GLYCEMIC TRAITS ,Diabetes Mellitus ,Animals ,Humans ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,Polymorphism ,SIGNATURES ,Genetic association study ,Aged ,CAUSAL VARIANTS ,geography ,Pancreatic islets ,Data acquisition ,General Chemistry ,Sequence Analysis, DNA ,DNA ,Gene regulation ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,Diacylglycerol Kinase/genetics/metabolism ,Expression quantitative trait loci ,lcsh:Q ,TYPE-2 DIABETES RISK ,3111 Biomedicine ,TCF7L2 ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
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., Mechanistic inference following GWAS is hampered by the lack of tissue-specific transcriptomic resources. Here the authors combine genetic variants predisposing to type 2 diabetes with human pancreatic islet RNA-seq data. They identify 7741 islet expression quantitative trait loci (eQTLs), providing a resource for functional interpretation of association signals mapping to non-coding sequence.
- Published
- 2020