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

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.

A Dual Systems Genetics Approach Identifies Common Genes, Networks, and Pathways for Type 1 and 2 Diabetes in Human Islets

“…Leveraging on a study by Vinuela and colleagues (Viñuela et al, 2020 ) that profiled gene expression and performed genotyping of human islets from 420 individual donors, we retrieved islet eQTLs. Both exon and gene-level cis -eQTLs corresponding to 4,312 and 6,039 genes, respectively (FDR < 1%; cis defined as within 1 Mb of the transcription start site [TSS]), were combined that resulted in a total of 10,108 islet eQTL associations for 6,618 genes (Table 1.1 in Supplementary File 1 ).…”

“…Recently, Viñuela et al ( 2020 ) profiled and genotyped human islet samples from 420 human organ donors as a part of Integrated Network for Systematic analysis of Pancreatic Islet RNA Expression (InsPIRE) consortium (Viñuela et al, 2020 ). The study aggregated previous islet studies and retrieved data from 196 individuals (Fadista et al, 2014 ; van de Bunt et al, 2015 ; Varshney et al, 2017 ).…”

Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity

“…To further explore the top associated variants, we extracted cis-expression quantitative trait loci (cis-eQTLs) associations from 43 GTEx tissues ( 22 ) and pancreatic islets from the InsPIRE study ( 23 ). Cis-eQTLs analysis is used to explore candidate genes mediating the activity of GWAS variants.…”

“…We show that the known loci for HbA1c, such as ABCB11 , and the established type 2 diabetes loci , IGF2BP2, and ARAP1 , could mediate their effect on type 2 diabetes risk by their action on pancreatic beta-cell glucose sensitivity. Previous literature has shown the association of these loci with glucose homeostasis and cis-eQTLs active in pancreatic islets ( 23 ). Insulin-like growth factor 2 (IGF2) mRNA-binding protein 2 ( IGF2BP2 ) belongs to a family of IGF2 mRNA-binding proteins that play an important role in pancreatic development ( 34 ), while IGF2BP2 mRNA levels are associated with glucose and insulin homeostasis ( 35 ).…”

“…To identify potential effector transcripts mediating the activity of the top associated variants, we extracted cis-expression quantitative trait loci (eQTLs) information available from each of the top associated SNPs in 43 GTEx tissues ( 22 ) and pancreatic islets ( 23 ). Since these studies reported multiple genes associated with each SNP, we selected the most strongly associated eQTLs per SNP that generated a nominal P value, before calculating a corrected P value with the p.adjust function in R and using the Bejamini-Hochberg method.…”