. 2023 Feb 2;110(2):284-299.

doi: 10.1016/j.ajhg.2023.01.002. Epub 2023 Jan 23.

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

K Alaine Broadaway¹, Xianyong Yin², Alice Williamson³, Victoria A Parsons¹, Emma P Wilson¹, Anne H Moxley¹, Swarooparani Vadlamudi¹, Arushi Varshney⁴, Anne U Jackson⁵, Vasudha Ahuja⁶, Stefan R Bornstein⁷, Laura J Corbin⁸, Graciela E Delgado⁹, Om P Dwivedi¹⁰, Lilian Fernandes Silva¹¹, Timothy M Frayling¹², Harald Grallert¹³, Stefan Gustafsson¹⁴, Liisa Hakaste⁶, Ulf Hammar¹⁵, Christian Herder¹⁶, Sandra Herrmann¹⁷, Kurt Højlund¹⁸, David A Hughes⁸, Marcus E Kleber¹⁹, Cecilia M Lindgren²⁰, Ching-Ti Liu²¹, Jian'an Luan²², Anni Malmberg²³, Angela P Moissl²⁴, Andrew P Morris²⁵, Nikolaos Perakakis⁷, Annette Peters²⁶, John R Petrie²⁷, Michael Roden²⁸, Peter E H Schwarz²⁹, Sapna Sharma³⁰, Angela Silveira³¹, Rona J Strawbridge³², Tiinamaija Tuomi³³, Andrew R Wood³⁴, Peitao Wu²¹, Björn Zethelius³⁵, Damiano Baldassarre³⁶, Johan G Eriksson³⁷, Tove Fall¹⁵, Jose C Florez³⁸, Andreas Fritsche³⁹, Bruna Gigante⁴⁰, Anders Hamsten⁴⁰, Eero Kajantie⁴¹, Markku Laakso¹¹, Jari Lahti²³, Deborah A Lawlor⁸, Lars Lind¹⁴, Winfried März⁴², James B Meigs⁴³, Johan Sundström¹⁴, Nicholas J Timpson⁸, Robert Wagner³⁹, Mark Walker⁴⁴, Nicholas J Wareham⁴⁵, Hugh Watkins⁴⁶, Inês Barroso⁴⁷, Stephen O'Rahilly⁴⁸, Niels Grarup⁴⁹, Stephen Cj Parker⁵⁰, Michael Boehnke², Claudia Langenberg⁵¹, Eleanor Wheeler⁵², Karen L Mohlke⁵³

Affiliations

¹ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
² Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
³ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK.
⁴ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁵ Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁶ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
⁷ Department of Internal Medicine, Metabolic and Vascular Medicine, MedicCal Faculty Carl Gustav Carus, Dresden, Germany; Helmholtz Zentrum München, Paul Langerhans Institute Dresden, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research, Neuherberg, Germany.
⁸ Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁹ Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany.
¹⁰ University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland.
¹¹ Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
¹² College of Medicine and Health, Exeter University, Exeter, UK.
¹³ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
¹⁴ Department of Medical Sciences, Clinical Epidemiology, Uppsala University, Uppsala, Sweden.
¹⁵ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹⁶ German Center for Diabetes Research, Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹⁷ Department of Internal Medicine, Prevention and Care of Diabetes, Medical Faculty Carl Gustav Carus, Dresden, Germany; Helmholtz Zentrum München, Paul Langerhans Institute Dresden, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany.
¹⁸ Steno Diabetes Center Odense, Odense, Denmark.
¹⁹ Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany; SYNLAB MVZ Humangenetik Mannheim, Mannheim, BW, Germany.
²⁰ Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK; Nuffield Department of Population Health, University of Oxford, Oxford, UK; Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, UK; Broad Institute, Cambridge, MA, USA.
²¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
²² MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
²³ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
²⁴ Institute of Nutritional Sciences, Friedrich-Schiller-University, Jena, Germany; Competence Cluster for Nutrition and Cardiovascular Health, Halle-Jena-Leipzig, Germany; Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany.
²⁵ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
²⁶ Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
²⁷ School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
²⁸ Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Neuherberg, Germany.
²⁹ Department of Internal Medicine, Prevention and Care of Diabetes, Medical Faculty Carl Gustav Carus, Dresden, Germany; Helmholtz Zentrum München, Paul Langerhans Institute Dresden, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research, Neuherberg, Germany.
³⁰ German Center for Diabetes Research, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Chair of Food Chemistry and Molecular Sensory Science, Technische Universität München, Freising, Germany.
³¹ Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden; Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
³² Institute of Health and Wellbeing, Mental Health and Wellbeing, University of Glasgow, Glasgow, UK; Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden.
³³ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Abdominal Center, Endocrinology, Helsinki University Hospital, Helsinki, Finland.
³⁴ Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK.
³⁵ Department of Geriatrics, Uppsala University, Uppsala, Sweden.
³⁶ Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy; Cardiovascular Prevention Area, Centro Cardiologico Monzino I.R.C.C.S., Milan, Italy.
³⁷ Department of General Practice and Primary Health Care, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland; Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.
³⁸ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
³⁹ Department of Internal Medicine, Diabetology, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany.
⁴⁰ Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden.
⁴¹ Population Health Unit, Finnish Institute for Health and Welfare, Helsinki, Finland; PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
⁴² Synlab Academy, SYNLAB Holding Deutschland GmbH, Mannheim, BW, Germany; Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany.
⁴³ Department of Medicine, Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁴⁴ Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
⁴⁵ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK; Health Data Research UK, Gibbs Building, London, UK.
⁴⁶ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁴⁷ Exeter Centre of Excellence for Diabetes Research, Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
⁴⁸ MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
⁴⁹ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁰ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
⁵¹ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK; Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany; Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
⁵² MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK. Electronic address: eleanor.wheeler@mrc-epid.cam.ac.uk.
⁵³ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. Electronic address: mohlke@med.unc.edu.

PMID: 36693378
PMCID: PMC9943750
DOI: 10.1016/j.ajhg.2023.01.002

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

K Alaine Broadaway et al. Am J Hum Genet. 2023.

. 2023 Feb 2;110(2):284-299.

doi: 10.1016/j.ajhg.2023.01.002. Epub 2023 Jan 23.

Authors

Affiliations

¹ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
² Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
³ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK.
⁴ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁵ Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁶ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
⁷ Department of Internal Medicine, Metabolic and Vascular Medicine, MedicCal Faculty Carl Gustav Carus, Dresden, Germany; Helmholtz Zentrum München, Paul Langerhans Institute Dresden, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research, Neuherberg, Germany.
⁸ Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁹ Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany.
¹⁰ University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland.
¹¹ Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
¹² College of Medicine and Health, Exeter University, Exeter, UK.
¹³ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
¹⁴ Department of Medical Sciences, Clinical Epidemiology, Uppsala University, Uppsala, Sweden.
¹⁵ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹⁶ German Center for Diabetes Research, Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹⁷ Department of Internal Medicine, Prevention and Care of Diabetes, Medical Faculty Carl Gustav Carus, Dresden, Germany; Helmholtz Zentrum München, Paul Langerhans Institute Dresden, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany.
¹⁸ Steno Diabetes Center Odense, Odense, Denmark.
¹⁹ Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany; SYNLAB MVZ Humangenetik Mannheim, Mannheim, BW, Germany.
²⁰ Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK; Nuffield Department of Population Health, University of Oxford, Oxford, UK; Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, UK; Broad Institute, Cambridge, MA, USA.
²¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
²² MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
²³ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
²⁴ Institute of Nutritional Sciences, Friedrich-Schiller-University, Jena, Germany; Competence Cluster for Nutrition and Cardiovascular Health, Halle-Jena-Leipzig, Germany; Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany.
²⁵ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
²⁶ Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
²⁷ School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
²⁸ Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Neuherberg, Germany.
²⁹ Department of Internal Medicine, Prevention and Care of Diabetes, Medical Faculty Carl Gustav Carus, Dresden, Germany; Helmholtz Zentrum München, Paul Langerhans Institute Dresden, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research, Neuherberg, Germany.
³⁰ German Center for Diabetes Research, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Chair of Food Chemistry and Molecular Sensory Science, Technische Universität München, Freising, Germany.
³¹ Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden; Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
³² Institute of Health and Wellbeing, Mental Health and Wellbeing, University of Glasgow, Glasgow, UK; Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden.
³³ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Abdominal Center, Endocrinology, Helsinki University Hospital, Helsinki, Finland.
³⁴ Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK.
³⁵ Department of Geriatrics, Uppsala University, Uppsala, Sweden.
³⁶ Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy; Cardiovascular Prevention Area, Centro Cardiologico Monzino I.R.C.C.S., Milan, Italy.
³⁷ Department of General Practice and Primary Health Care, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland; Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.
³⁸ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
³⁹ Department of Internal Medicine, Diabetology, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany.
⁴⁰ Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden.
⁴¹ Population Health Unit, Finnish Institute for Health and Welfare, Helsinki, Finland; PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
⁴² Synlab Academy, SYNLAB Holding Deutschland GmbH, Mannheim, BW, Germany; Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany.
⁴³ Department of Medicine, Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁴⁴ Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
⁴⁵ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK; Health Data Research UK, Gibbs Building, London, UK.
⁴⁶ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁴⁷ Exeter Centre of Excellence for Diabetes Research, Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
⁴⁸ MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
⁴⁹ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁰ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
⁵¹ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK; Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany; Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
⁵² MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK. Electronic address: eleanor.wheeler@mrc-epid.cam.ac.uk.
⁵³ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. Electronic address: mohlke@med.unc.edu.

PMID: 36693378
PMCID: PMC9943750
DOI: 10.1016/j.ajhg.2023.01.002

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.

Keywords: GWAS; colocalization; conditional; eQTL; enhancer; fine-mapping; meta-analysis; proinsulin; signal; type 2 diabetes.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests J.B.M. is an academic associate for Quest Diagnostics Endocrine R&D. M.E.K. is employed by SYNLAB Holding Deutschland GmbH. C.M.L. receives grants from Bayer Ag and Novo Nordisk and her husband works for Vertex. B.Z. is employed at the Swedish Medical Products Agency, SE-751 03 Uppsala, Sweden; the views expressed in this paper are the personal views of the authors and not necessarily the views of the Swedish government agency. B.Z. has not received any funding or benefits from any sponsor for the present work. J.C.F. receives consulting honoraria from Goldfinch Bio and AstraZeneca and speaker honoraria from Novo Nordisk, AstraZeneca, and Merck for research lectures over which he had full control on content. D.A.L. has received support from Medtronics Ltd and Roche Diagnostics for research unrelated to this paper. W.M. reports grants and personal fees from Siemens Diagnostics, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants and personal fees from AstraZeneca, grants and personal fees from Danone Research, grants and personal fees from Sanofi, personal fees from Hoffmann LaRoche, personal fees from MSD, grants and personal fees from Pfizer, personal fees from Synageva, grants and personal fees from BASF, grants from Abbott Diagnostics, and grants and personal fees from Numares, outside the submitted work. W.M. is employed by Synlab Holding Deutschland GmbH. R.W. reports lecture fees from Novo Nordisk and Sanofi and served on an advisory board for Akcea Therapeutics, Daiichi Sankyo, Sanofi, and Novo Nordisk. E.W. is now an employee of AstraZeneca.

Figures

**Figure 1**
Direction of allelic effect of fasting glucose versus fasting proinsulin Standardized effect sizes for lead variants are shown from this study compared to fasting glucose from Chen et al. (2021). Left of the vertical line, alleles associated with higher fasting glucose and lower proinsulin; right of the vertical line, alleles associated with higher fasting glucose and higher proinsulin.

**Figure 2**
The ANK1/NKX6-3 locus associations with proinsulin, T2D, and adipose ANK1 expression The proinsulin signal at this locus colocalizes with the second AGEN T2D signal and the METSIM adipose ANK1 eQTL signal (HyPrColoc PPFC = 0.92). We used approximate conditional analysis results for the AGEN second signal in HyPrColoc as well as for the plot shown above. AGEN results colored by ASN 1000 Genomes LD reference.

**Figure 3**
Candidate variants may influence regulatory activity (A) Regulatory element enrichment analyses using enhancers, accessible chromatin, and other data from islets, skeletal muscle, and adipose. Proinsulin variants are enriched in islet active enhancers and accessible chromatin, especially in beta cells. (B) The *MADD* locus in proinsulin, lead variant rs10501320. The *MADD* region is an area of extensive LD—the full locus is shown in Figure S4. (C) The lead variant of the primary *MADD* signal is located in an intron of *MADD* and is in accessible chromatin in islets and an enhancer state and a region conserved across species. (D) A 411-bp genomic element spanning the lead variant rs10501320 showed strong enhancer activity in a transcriptional reporter assay in two beta cell lines: MIN6 and 832/13. EV, empty vector; G/C, alleles at the lead variant rs10501320. In the eQTL and GWAS data, the G allele at rs10501320 that showed higher transcriptional activity showed higher *MADD* expression levels in islets and is associated with higher proinsulin. Bars show standard errors; p values correspond to two-sided t tests.

See this image and copyright information in PMC

References

1. Porte D. Banting lecture 1990. Beta-cells in type II diabetes mellitus. Diabetes. 1991;40:166–180. - PubMed
1. Ward W.K., Bolgiano D.C., McKnight B., Halter J.B., Porte D. Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J. Clin. Invest. 1984;74:1318–1328. - PMC - PubMed
1. Mezza T., Ferraro P.M., Sun V.A., Moffa S., Cefalo C.M.A., Quero G., Cinti F., Sorice G.P., Pontecorvi A., Folli F., et al. Increased β-cell workload modulates proinsulin-to-insulin ratio in humans. Diabetes. 2018;67:2389–2396. - PubMed
1. Liu M., Weiss M.A., Arunagiri A., Yong J., Rege N., Sun J., Haataja L., Kaufman R.J., Arvan P. Biosynthesis, structure, and folding of the insulin precursor protein. Diabetes, Obes. Metab. 2018;20:28–50. - PMC - PubMed
1. Strawbridge R.J., Dupuis J., Prokopenko I., Barker A., Ahlqvist E., Rybin D., Petrie J.R., Travers M.E., Bouatia-Naji N., Dimas A.S., et al. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. Diabetes. 2011;60:2624–2634. - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical