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Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Broadaway, K Alaine 
Yin, Xianyong 
Williamson, Alice 
Parsons, Victoria A 
Wilson, Emma P 

Abstract

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Description

Keywords

GWAS, colocalization, conditional, eQTL, enhancer, fine-mapping, meta-analysis, proinsulin, signal, type 2 diabetes, Humans, Proinsulin, Diabetes Mellitus, Type 2, Genome-Wide Association Study, Insulin, Glucose, Transcription Factors, Homeodomain Proteins

Journal Title

Am J Hum Genet

Conference Name

Journal ISSN

0002-9297
1537-6605

Volume Title

110

Publisher

Elsevier BV
Sponsorship
MRC (MC_UU_00006/1)
MRC (MC_UU_00014/5)