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Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D.

McCarthy, Mark I
CollaborationWith : Brown, Andrew Anand / Howald, Cédric / Panousis, Nikolaos / Dermitzakis, Emmanouil
Published in Nature communications. 2020, vol. 11, no. 1, 4912
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.
Keywords AdolescentAdultAged80 and overAnimalsBlood Glucose/genetics/metabolismCell LineTumorCohort StudiesDiabetes MellitusType 2/blood/geneticsDiacylglycerol Kinase/genetics/metabolismEnhancer ElementsGeneticFemaleGene Expression RegulationGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansIslets of Langerhans/metabolismMaleMiceMiddle AgedPolymorphismSingle NucleotideQuantitative Trait LociRNA-SeqSequence AnalysisDNATranscription Factor 7-Like 2 Protein/genetics/metabolismYoung Adult
PMID: 32999275
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Research group Population Genomics and Genetics of Complex Traits (892)
Swiss National Science Foundation: 31003A_149984
European Commission: DIRECT
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VINUELA RODRIGUEZ, Ana, MCCARTHY, Mark I. Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D. In: Nature Communications, 2020, vol. 11, n° 1, p. 4912. doi: 10.1038/s41467-020-18581-8 https://archive-ouverte.unige.ch/unige:144670

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Deposited on : 2020-11-12

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