University of Oulu

Broadaway, K. A., Yin, X., Williamson, A., Parsons, V. A., Wilson, E. P., Moxley, A. H., Vadlamudi, S., Varshney, A., Jackson, A. U., Ahuja, V., Bornstein, S. R., Corbin, L. J., Delgado, G. E., Dwivedi, O. P., Fernandes Silva, L., Frayling, T. M., Grallert, H., Gustafsson, S., Hakaste, L., … Mohlke, K. L. (2023). Loci for insulin processing and secretion provide insight into type 2 diabetes risk. The American Journal of Human Genetics, 110(2), 284–299.

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

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Author: Broadaway, K. Alaine1; Yin, Xianyong2,3; Williamson, Alice4,5;
Organizations: 1Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA.
2Univ Michigan, Dept Biostat, Ann Arbor, MI USA.
3Univ Michigan, Ctr Stat Genet, Ann Arbor, MI USA.
4Univ Cambridge, Inst Metab Sci, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England.
5Univ Cambridge, Univ Cambridge Metab Res Labs, Wellcome MRC Inst Metab Sci, Dept Clin Biochem, Cambridge, England.
6Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI USA.
7Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.
8Med Fac Carl Gustav Carus, Dept Internal Med Metab & Vasc Med, Dresden, Germany.
9Tech Univ Dresden, Univ Hosp, Paul Langerhans Inst Dresden, Helmholtz Zentrum Munchen, Dresden, Germany.
10Tech Univ Dresden, Fac Med, Dresden, Germany.
11German Ctr Diabet Res, Neuherberg, Germany.
12Univ Bristol, Integrat Epidemiol Unit, Med Res Council, Bristol, England.
13Heidelberg Univ, Med Fac Mannheim, Mannheim, Germany.
14Univ Helsinki, Helsinki, Finland.
15Folkhalsan Res Ctr, Helsinki, Finland.
16Univ Eastern Finland, Inst Clin Med, Kuopio, Finland.
17Exeter Univ, Coll Med & Hlth, Exeter, England.
18Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany.
19Uppsala Univ, Dept Med Sci, Clin Epidemiol, Uppsala, Sweden.
20Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden.
21Heinrich Heine Univ Dusseldorf, Leibniz Ctr Diabet Res, Inst Clin Diabetol, German Dia betes Ctr, Dusseldorf, Germany.
22Heinrich Heine Univ Dusseldorf, Med Fac, Dept Endocrinol & Diabetol, Dusseldorf, Germany.
23Heinrich Heine Univ Dusseldorf, Univ Hosp Dusseldorf, Dusseldorf, Germany.
24Med Fac Carl Gustav Carus, Dept Internal Med Prevent & Care Diabet, Dresden, Germany.
25Steno Diabet Ctr Odense, Odense, Denmark.
26Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, England.
27SYNLAB MVZ Humangenet Mannheim, Mannheim, BW, Germany.
28Univ Oxford, Oxford Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England.
29Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England.
30Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
31Broad Inst, Cambridge, MA USA.
32Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.
33Univ Helsinki, Fac Med, Dept Psychol & Logoped, Helsinki, Finland.
34Friedrich Schiller Univ, Inst Nutr Sci, Jena, Germany.
35Competence Cluster Nutr & Cardiovasc Hlth, Leipzig, Germany.
36Univ Manchester, Ctr Genet & Genom Versus Arthrit, Ctr Musculoskeletal Res, Manchester, England.
37Univ Glasgow, Sch Hlth & Wellbeing, Glasgow City, England.
38Helmholtz Zentrum Munich, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany.
39Tech Univ Munich Freising, Chair Food Chem & Mol Sensory Sci, Munich, Germany.
40Karolinska Inst, Dept Med Solna, Div Cardiovasc Med, Stockholm, Sweden.
41Univ Oxford, Oxford Biomed Res Ctr, Wellcome Ctr Human Genet, Oxford, England.
42Univ Glasgow, Inst Hlth & Wellbeing, Mental Hlth & Well being, Glasgow City, England.
43Helsinki Univ Hosp, Abdominal Ctr, Endocrinol, Helsinki, Finland.
44Univ Exeter, Coll Med & Hlth, Genet Complex Traits, Exeter, England.
45Uppsala Univ, Dept Geriatr, Uppsala, Sweden.
46Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy.
47Ctr Cardiol Monzino IRCCS, Cardiovasc Prevent Area, Milan, Italy.
48Univ Helsinki, Fac Med, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.
49Folkhglsan Res Ctr, Helsinki, Finland.
50Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Obstet & Gynecol, Singapore, Singapore.
51Massachusetts Gen Hosp, Diabet Unit, Boston, MA USA.
52Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA USA.
53Broad Inst, Programs Metab & Med & Populat Genet, Cambridge, MA USA.
54Harvard Med Sch, Dept Med, Boston, MA USA.
55Dept Internal Med, Diabetol, Tubingen, Germany.
56Univ Tubingen, Inst Diabet Res & Metab Dis, Helmholtz Ctr Munich, Tubingen, Germany.
57Finnish Inst Hlth & Welf, Populat Hlth Unit, Helsinki, Finland.
58Oulu Univ Hosp, PEDEGO Res Unit, MRC Oulu, Oulu, Finland.
59Univ Oulu, Oulu, Finland.
60Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway.
61Helsinki Univ Hosp, Childrens Hosp, Helsinki, Finland.
62Synlab Acad, SYNLAB Holding Deutschland GmbH, Mannheim, BW, Germany.
63Massachusetts Gen Hosp, Dept Med, Div Gen Internal Med, Boston, MA USA.
64Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.
65Newcastle Univ, Fac Med Sci, Newcastle Upon Tyne, England.
66Hlth Data Res UK, Gibbs Bldg, London, England.
67Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England.
68Univ Exeter, Univ Exeter Med Sch, Exeter Ctr Excellence Diabet Res Genet Complex Tr, Exeter, England.
69Univ Cambridge, Wellcome Trust Med Res Council Inst Metab Sci, MRC Metab Dis Unit, Cambridge, England.
70Univ Copenhagen, Novo Nord Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark.
71Univ Michigan, Dept Human Genet, Ann Arbor, MI USA.
72Charite Univ med Berlin, Berlin Inst Hlth, Computat Med, Berlin, Germany.
73Queen Mary Univ London, Precis Healthcare Univ Res Inst, London, England.
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 1.3 MB)
Persistent link:
Language: English
Published: Elsevier, 2023
Publish Date: 2023-10-04


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.

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Series: American journal of human genetics
ISSN: 0002-9297
ISSN-E: 1537-6605
ISSN-L: 0002-9297
Volume: 110
Issue: 2
Pages: 284 - 299
DOI: 10.1016/j.ajhg.2023.01.002
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
Dataset Reference: Upon publication, GWAS summary statistics will be available on the MAGIC Investigators website, and through the Common Metabolic Diseases knowledge portal.
Copyright information: © 2023 American Society of Human Genetics. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http:/