Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

Alice Williamson; Dougall M. Norris; Xianyong Yin; K. Alaine Broadaway; Anne H. Moxley; Swarooparani Vadlamudi; Emma P. Wilson; Anne U. Jackson; Vasudha Ahuja; Mette K. Andersen; Zorayr Arzumanyan; Lori L. Bonnycastle; Stefan R. Bornstein; Maxi P. Bretschneider; Thomas A. Buchanan; Yi Cheng Chang; Lee Ming Chuang; Ren Hua Chung; Tine D. Clausen; Peter Damm; Graciela E. Delgado; Vanessa D. de Mello; Josée Dupuis; Om P. Dwivedi; Michael R. Erdos; Lilian Fernandes Silva; Timothy M. Frayling; Christian Gieger; Mark O. Goodarzi; Xiuqing Guo; Stefan Gustafsson; Liisa Hakaste; Ulf Hammar; Gad Hatem; Sandra Herrmann; Kurt Højlund; Katrin Horn; Willa A. Hsueh; Yi Jen Hung; Chii Min Hwu; Anna Jonsson; Line L. Kårhus; Marcus E. Kleber; Peter Kovacs; Timo A. Lakka; Marie Lauzon; I. Te Lee; Cecilia M. Lindgren; Jaana Lindström; The Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC); Torben Hansen

doi:10.1038/s41588-023-01408-9

Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

Alice Williamson, Dougall M. Norris, Xianyong Yin, K. Alaine Broadaway, Anne H. Moxley, Swarooparani Vadlamudi, Emma P. Wilson, Anne U. Jackson, Vasudha Ahuja, Mette K. Andersen, Zorayr Arzumanyan, Lori L. Bonnycastle, Stefan R. Bornstein, Maxi P. Bretschneider, Thomas A. Buchanan, Yi Cheng Chang, Lee Ming Chuang, Ren Hua Chung, Tine D. Clausen, Peter DammGraciela E. Delgado, Vanessa D. de Mello, Josée Dupuis, Om P. Dwivedi, Michael R. Erdos, Lilian Fernandes Silva, Timothy M. Frayling, Christian Gieger, Mark O. Goodarzi, Xiuqing Guo, Stefan Gustafsson, Liisa Hakaste, Ulf Hammar, Gad Hatem, Sandra Herrmann, Kurt Højlund, Katrin Horn, Willa A. Hsueh, Yi Jen Hung, Chii Min Hwu, Anna Jonsson, Line L. Kårhus, Marcus E. Kleber, Peter Kovacs, Timo A. Lakka, Marie Lauzon, I. Te Lee, Cecilia M. Lindgren, Jaana Lindström, The Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), Torben Hansen

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Abstract

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10⁻⁸) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	55
Udgave nummer	6
Sider (fra-til)	973-983
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-023-01408-9
Status	Udgivet - jun. 2023

Bibliografisk note

Funding Information:
All data used in genetic risk score association analyses are available from the UK Biobank upon application ( https://www.ukbiobank.ac.uk ). All analyses in the UK Biobank in this manuscript were conducted under application 44448. Further details about the RISC study and data availability can be found here: http://www.egir.org/egirrisc/ . The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. The data used for the analyses described in this manuscript can be obtained from the GTEx Portal ( https://www.gtexportal.org/home/ ) and dbGaP accession number phs000424.v8.p2 . Genome regulatory annotations from ENCODE ( https://www.encodeproject.org/ ) and Roadmap Epigenomics Consortium ( https://egg2.wustl.edu/roadmap/web_portal/ ) were explored via UCSC Genome Browser ( http://genome.ucsc.edu ). Published differentiated 3T3-L1 RNA-sequencing data used in this study are available from GEO accession GSE129957 ( https://www.ncbi.nlm.nih.gov/geo/ ). are provided with this paper.

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

Dokumenter og links

10.1038/s41588-023-01408-9

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7614755/pdf/EMS178611.pdf

Citationsformater

Williamson, A., Norris, D. M., Yin, X., Broadaway, K. A., Moxley, A. H., Vadlamudi, S., Wilson, E. P., Jackson, A. U., Ahuja, V., Andersen, M. K., Arzumanyan, Z., Bonnycastle, L. L., Bornstein, S. R., Bretschneider, M. P., Buchanan, T. A., Chang, Y. C., Chuang, L. M., Chung, R. H., Clausen, T. D., ... Hansen, T. (2023). Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake. Nature Genetics, 55(6), 973-983. https://doi.org/10.1038/s41588-023-01408-9

@article{d7102fe0a511494baab0ef8ac9b32692,

title = "Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake",

abstract = "Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10−8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.",

keywords = "Blood Glucose/genetics, Diabetes Mellitus, Type 2/genetics, Genome-Wide Association Study, Glucose/metabolism, Humans, Insulin Resistance/genetics, Insulin/genetics",

author = "Alice Williamson and Norris, {Dougall M.} and Xianyong Yin and Broadaway, {K. Alaine} and Moxley, {Anne H.} and Swarooparani Vadlamudi and Wilson, {Emma P.} and Jackson, {Anne U.} and Vasudha Ahuja and Andersen, {Mette K.} and Zorayr Arzumanyan and Bonnycastle, {Lori L.} and Bornstein, {Stefan R.} and Bretschneider, {Maxi P.} and Buchanan, {Thomas A.} and Chang, {Yi Cheng} and Chuang, {Lee Ming} and Chung, {Ren Hua} and Clausen, {Tine D.} and Peter Damm and Delgado, {Graciela E.} and {de Mello}, {Vanessa D.} and Jos{\'e}e Dupuis and Dwivedi, {Om P.} and Erdos, {Michael R.} and Silva, {Lilian Fernandes} and Frayling, {Timothy M.} and Christian Gieger and Goodarzi, {Mark O.} and Xiuqing Guo and Stefan Gustafsson and Liisa Hakaste and Ulf Hammar and Gad Hatem and Sandra Herrmann and Kurt H{\o}jlund and Katrin Horn and Hsueh, {Willa A.} and Hung, {Yi Jen} and Hwu, {Chii Min} and Anna Jonsson and K{\aa}rhus, {Line L.} and Kleber, {Marcus E.} and Peter Kovacs and Lakka, {Timo A.} and Marie Lauzon and Lee, {I. Te} and Lindgren, {Cecilia M.} and Jaana Lindstr{\"o}m and {The Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)} and Torben Hansen",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = jun,

doi = "10.1038/s41588-023-01408-9",

language = "English",

volume = "55",

pages = "973--983",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

Williamson, A, Norris, DM, Yin, X, Broadaway, KA, Moxley, AH, Vadlamudi, S, Wilson, EP, Jackson, AU, Ahuja, V, Andersen, MK, Arzumanyan, Z, Bonnycastle, LL, Bornstein, SR, Bretschneider, MP, Buchanan, TA, Chang, YC, Chuang, LM, Chung, RH, Clausen, TD, Damm, P, Delgado, GE, de Mello, VD, Dupuis, J, Dwivedi, OP, Erdos, MR, Silva, LF, Frayling, TM, Gieger, C, Goodarzi, MO, Guo, X, Gustafsson, S, Hakaste, L, Hammar, U, Hatem, G, Herrmann, S, Højlund, K, Horn, K, Hsueh, WA, Hung, YJ, Hwu, CM, Jonsson, A, Kårhus, LL, Kleber, ME, Kovacs, P, Lakka, TA, Lauzon, M, Lee, IT, Lindgren, CM, Lindström, J, The Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) & Hansen, T 2023, 'Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake', Nature Genetics, bind 55, nr. 6, s. 973-983. https://doi.org/10.1038/s41588-023-01408-9

TY - JOUR

T1 - Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

AU - Williamson, Alice

AU - Norris, Dougall M.

AU - Yin, Xianyong

AU - Broadaway, K. Alaine

AU - Moxley, Anne H.

AU - Vadlamudi, Swarooparani

AU - Wilson, Emma P.

AU - Jackson, Anne U.

AU - Ahuja, Vasudha

AU - Andersen, Mette K.

AU - Arzumanyan, Zorayr

AU - Bonnycastle, Lori L.

AU - Bornstein, Stefan R.

AU - Bretschneider, Maxi P.

AU - Buchanan, Thomas A.

AU - Chang, Yi Cheng

AU - Chuang, Lee Ming

AU - Chung, Ren Hua

AU - Clausen, Tine D.

AU - Damm, Peter

AU - Delgado, Graciela E.

AU - de Mello, Vanessa D.

AU - Dupuis, Josée

AU - Dwivedi, Om P.

AU - Erdos, Michael R.

AU - Silva, Lilian Fernandes

AU - Frayling, Timothy M.

AU - Gieger, Christian

AU - Goodarzi, Mark O.

AU - Guo, Xiuqing

AU - Gustafsson, Stefan

AU - Hakaste, Liisa

AU - Hammar, Ulf

AU - Hatem, Gad

AU - Herrmann, Sandra

AU - Højlund, Kurt

AU - Horn, Katrin

AU - Hsueh, Willa A.

AU - Hung, Yi Jen

AU - Hwu, Chii Min

AU - Jonsson, Anna

AU - Kårhus, Line L.

AU - Kleber, Marcus E.

AU - Kovacs, Peter

AU - Lakka, Timo A.

AU - Lauzon, Marie

AU - Lee, I. Te

AU - Lindgren, Cecilia M.

AU - Lindström, Jaana

AU - The Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)

AU - Hansen, Torben

PY - 2023/6

Y1 - 2023/6

N2 - Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10−8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

AB - Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10−8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

KW - Blood Glucose/genetics

KW - Diabetes Mellitus, Type 2/genetics

KW - Genome-Wide Association Study

KW - Glucose/metabolism

KW - Humans

KW - Insulin Resistance/genetics

KW - Insulin/genetics

U2 - 10.1038/s41588-023-01408-9

DO - 10.1038/s41588-023-01408-9

M3 - Journal article

C2 - 37291194

AN - SCOPUS:85161434094

SN - 1061-4036

VL - 55

SP - 973

EP - 983

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

Abstract

Bibliografisk note

Dokumenter og links

Fingeraftryk

Citationsformater