[HTML][HTML] Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D

A Viñuela, A Varshney, M van de Bunt… - Nature …, 2020 - nature.com
Nature communications, 2020nature.com
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 …
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.
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