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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Loci for insulin processing and secretion provide insight into type 2 diabetes risk. / Broadaway, K. Alaine; Yin, Xianyong; Williamson, Alice; Parsons, Victoria A.; Wilson, Emma P.; Moxley, Anne H.; Vadlamudi, Swarooparani; Varshney, Arushi; Jackson, Anne U.; Ahuja, Vasudha; Bornstein, Stefan R.; Corbin, Laura J.; Delgado, Graciela E.; Dwivedi, Om P.; Silva, Lilian Fernandes; Frayling, Timothy M.; Grallert, Harald; Gustafsson, Stefan; Hakaste, Liisa; Hammar, Ulf; Herder, Christian; Herrmann, Sandra; Højlund, Kurt; Hughes, David A.; Kleber, Marcus E.; Lindgren, Cecilia M.; Liu, Ching Ti; Luan, Jian'an; Malmberg, Anni; Moissl, Angela P.; Morris, Andrew P.; Perakakis, Nikolaos; Peters, Annette; Petrie, John R.; Roden, Michael; Schwarz, Peter E.H.; Sharma, Sapna; Silveira, Angela; Strawbridge, Rona J.; Tuomi, Tiinamaija; Wood, Andrew R.; Wu, Peitao; Zethelius, Björn; Baldassarre, Damiano; Eriksson, Johan G.; Fall, Tove; Florez, Jose C.; Fritsche, Andreas; Gigante, Bruna; Hamsten, Anders; Kajantie, Eero; Laakso, Markku; Lahti, Jari; Lawlor, Deborah A.; Lind, Lars; März, Winfried; Meigs, James B.; Sundström, Johan; Timpson, Nicholas J.; Wagner, Robert; Walker, Mark; Wareham, Nicholas J.; Watkins, Hugh; Barroso, Inês; O'Rahilly, Stephen; Grarup, Niels; Parker, Stephen Cj; Boehnke, Michael; Langenberg, Claudia; Wheeler, Eleanor; Mohlke, Karen L.

In: American Journal of Human Genetics, Vol. 110, No. 2, 2023, p. 284-299.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Broadaway, KA, Yin, X, Williamson, A, Parsons, VA, Wilson, EP, Moxley, AH, Vadlamudi, S, Varshney, A, Jackson, AU, Ahuja, V, Bornstein, SR, Corbin, LJ, Delgado, GE, Dwivedi, OP, Silva, LF, Frayling, TM, Grallert, H, Gustafsson, S, Hakaste, L, Hammar, U, Herder, C, Herrmann, S, Højlund, K, Hughes, DA, Kleber, ME, Lindgren, CM, Liu, CT, Luan, J, Malmberg, A, Moissl, AP, Morris, AP, Perakakis, N, Peters, A, Petrie, JR, Roden, M, Schwarz, PEH, Sharma, S, Silveira, A, Strawbridge, RJ, Tuomi, T, Wood, AR, Wu, P, Zethelius, B, Baldassarre, D, Eriksson, JG, Fall, T, Florez, JC, Fritsche, A, Gigante, B, Hamsten, A, Kajantie, E, Laakso, M, Lahti, J, Lawlor, DA, Lind, L, März, W, Meigs, JB, Sundström, J, Timpson, NJ, Wagner, R, Walker, M, Wareham, NJ, Watkins, H, Barroso, I, O'Rahilly, S, Grarup, N, Parker, SC, Boehnke, M, Langenberg, C, Wheeler, E & Mohlke, KL 2023, 'Loci for insulin processing and secretion provide insight into type 2 diabetes risk', American Journal of Human Genetics, vol. 110, no. 2, pp. 284-299. https://doi.org/10.1016/j.ajhg.2023.01.002

APA

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., Silva, L. F., 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. American Journal of Human Genetics, 110(2), 284-299. https://doi.org/10.1016/j.ajhg.2023.01.002

Vancouver

Broadaway KA, Yin X, Williamson A, Parsons VA, Wilson EP, Moxley AH et al. Loci for insulin processing and secretion provide insight into type 2 diabetes risk. American Journal of Human Genetics. 2023;110(2):284-299. https://doi.org/10.1016/j.ajhg.2023.01.002

Author

Broadaway, K. Alaine ; Yin, Xianyong ; Williamson, Alice ; Parsons, Victoria A. ; Wilson, Emma P. ; Moxley, Anne H. ; Vadlamudi, Swarooparani ; Varshney, Arushi ; Jackson, Anne U. ; Ahuja, Vasudha ; Bornstein, Stefan R. ; Corbin, Laura J. ; Delgado, Graciela E. ; Dwivedi, Om P. ; Silva, Lilian Fernandes ; Frayling, Timothy M. ; Grallert, Harald ; Gustafsson, Stefan ; Hakaste, Liisa ; Hammar, Ulf ; Herder, Christian ; Herrmann, Sandra ; Højlund, Kurt ; Hughes, David A. ; Kleber, Marcus E. ; Lindgren, Cecilia M. ; Liu, Ching Ti ; Luan, Jian'an ; Malmberg, Anni ; Moissl, Angela P. ; Morris, Andrew P. ; Perakakis, Nikolaos ; Peters, Annette ; Petrie, John R. ; Roden, Michael ; Schwarz, Peter E.H. ; Sharma, Sapna ; Silveira, Angela ; Strawbridge, Rona J. ; Tuomi, Tiinamaija ; Wood, Andrew R. ; Wu, Peitao ; Zethelius, Björn ; Baldassarre, Damiano ; Eriksson, Johan G. ; Fall, Tove ; Florez, Jose C. ; Fritsche, Andreas ; Gigante, Bruna ; Hamsten, Anders ; Kajantie, Eero ; Laakso, Markku ; Lahti, Jari ; Lawlor, Deborah A. ; Lind, Lars ; März, Winfried ; Meigs, James B. ; Sundström, Johan ; Timpson, Nicholas J. ; Wagner, Robert ; Walker, Mark ; Wareham, Nicholas J. ; Watkins, Hugh ; Barroso, Inês ; O'Rahilly, Stephen ; Grarup, Niels ; Parker, Stephen Cj ; Boehnke, Michael ; Langenberg, Claudia ; Wheeler, Eleanor ; Mohlke, Karen L. / Loci for insulin processing and secretion provide insight into type 2 diabetes risk. In: American Journal of Human Genetics. 2023 ; Vol. 110, No. 2. pp. 284-299.

Bibtex

@article{6d193242e1174cc09e502cf8cd576a07,
title = "Loci for insulin processing and secretion provide insight into type 2 diabetes risk",
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 = "colocalization, conditional, enhancer, eQTL, fine-mapping, GWAS, meta-analysis, proinsulin, signal, type 2 diabetes",
author = "Broadaway, {K. Alaine} and Xianyong Yin and Alice Williamson and Parsons, {Victoria A.} and Wilson, {Emma P.} and Moxley, {Anne H.} and Swarooparani Vadlamudi and Arushi Varshney and Jackson, {Anne U.} and Vasudha Ahuja and Bornstein, {Stefan R.} and Corbin, {Laura J.} and Delgado, {Graciela E.} and Dwivedi, {Om P.} and Silva, {Lilian Fernandes} and Frayling, {Timothy M.} and Harald Grallert and Stefan Gustafsson and Liisa Hakaste and Ulf Hammar and Christian Herder and Sandra Herrmann and Kurt H{\o}jlund and Hughes, {David A.} and Kleber, {Marcus E.} and Lindgren, {Cecilia M.} and Liu, {Ching Ti} and Jian'an Luan and Anni Malmberg and Moissl, {Angela P.} and Morris, {Andrew P.} and Nikolaos Perakakis and Annette Peters and Petrie, {John R.} and Michael Roden and Schwarz, {Peter E.H.} and Sapna Sharma and Angela Silveira and Strawbridge, {Rona J.} and Tiinamaija Tuomi and Wood, {Andrew R.} and Peitao Wu and Bj{\"o}rn Zethelius and Damiano Baldassarre and Eriksson, {Johan G.} and Tove Fall and Florez, {Jose C.} and Andreas Fritsche and Bruna Gigante and Anders Hamsten and Eero Kajantie and Markku Laakso and Jari Lahti and Lawlor, {Deborah A.} and Lars Lind and Winfried M{\"a}rz and Meigs, {James B.} and Johan Sundstr{\"o}m and Timpson, {Nicholas J.} and Robert Wagner and Mark Walker and Wareham, {Nicholas J.} and Hugh Watkins and In{\^e}s Barroso and Stephen O'Rahilly and Niels Grarup and Parker, {Stephen Cj} and Michael Boehnke and Claudia Langenberg and Eleanor Wheeler and Mohlke, {Karen L.}",
note = "Publisher Copyright: Copyright {\textcopyright} 2023 American Society of Human Genetics. All rights reserved.",
year = "2023",
doi = "10.1016/j.ajhg.2023.01.002",
language = "English",
volume = "110",
pages = "284--299",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

RIS

TY - JOUR

T1 - Loci for insulin processing and secretion provide insight into type 2 diabetes risk

AU - Broadaway, K. Alaine

AU - Yin, Xianyong

AU - Williamson, Alice

AU - Parsons, Victoria A.

AU - Wilson, Emma P.

AU - Moxley, Anne H.

AU - Vadlamudi, Swarooparani

AU - Varshney, Arushi

AU - Jackson, Anne U.

AU - Ahuja, Vasudha

AU - Bornstein, Stefan R.

AU - Corbin, Laura J.

AU - Delgado, Graciela E.

AU - Dwivedi, Om P.

AU - Silva, Lilian Fernandes

AU - Frayling, Timothy M.

AU - Grallert, Harald

AU - Gustafsson, Stefan

AU - Hakaste, Liisa

AU - Hammar, Ulf

AU - Herder, Christian

AU - Herrmann, Sandra

AU - Højlund, Kurt

AU - Hughes, David A.

AU - Kleber, Marcus E.

AU - Lindgren, Cecilia M.

AU - Liu, Ching Ti

AU - Luan, Jian'an

AU - Malmberg, Anni

AU - Moissl, Angela P.

AU - Morris, Andrew P.

AU - Perakakis, Nikolaos

AU - Peters, Annette

AU - Petrie, John R.

AU - Roden, Michael

AU - Schwarz, Peter E.H.

AU - Sharma, Sapna

AU - Silveira, Angela

AU - Strawbridge, Rona J.

AU - Tuomi, Tiinamaija

AU - Wood, Andrew R.

AU - Wu, Peitao

AU - Zethelius, Björn

AU - Baldassarre, Damiano

AU - Eriksson, Johan G.

AU - Fall, Tove

AU - Florez, Jose C.

AU - Fritsche, Andreas

AU - Gigante, Bruna

AU - Hamsten, Anders

AU - Kajantie, Eero

AU - Laakso, Markku

AU - Lahti, Jari

AU - Lawlor, Deborah A.

AU - Lind, Lars

AU - März, Winfried

AU - Meigs, James B.

AU - Sundström, Johan

AU - Timpson, Nicholas J.

AU - Wagner, Robert

AU - Walker, Mark

AU - Wareham, Nicholas J.

AU - Watkins, Hugh

AU - Barroso, Inês

AU - O'Rahilly, Stephen

AU - Grarup, Niels

AU - Parker, Stephen Cj

AU - Boehnke, Michael

AU - Langenberg, Claudia

AU - Wheeler, Eleanor

AU - Mohlke, Karen L.

N1 - Publisher Copyright: Copyright © 2023 American Society of Human Genetics. All rights reserved.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - colocalization

KW - conditional

KW - enhancer

KW - eQTL

KW - fine-mapping

KW - GWAS

KW - meta-analysis

KW - proinsulin

KW - signal

KW - type 2 diabetes

U2 - 10.1016/j.ajhg.2023.01.002

DO - 10.1016/j.ajhg.2023.01.002

M3 - Journal article

C2 - 36693378

AN - SCOPUS:85147458360

VL - 110

SP - 284

EP - 299

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -

ID: 336466655