Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

Natalia Pervjakova; Gunn-Helen Moen; Maria-Carolina Borges; Teresa Ferreira; James P Cook; Catherine Allard; Robin N Beaumont; Mickaël Canouil; Gad Hatem; Anni Heiskala; Anni Joensuu; Ville Karhunen; Soo Heon Kwak; Frederick T J Lin; Jun Liu; Sheryl Rifas-Shiman; Claudia H Tam; Wing Hung Tam; Gudmar Thorleifsson; Toby Andrew; Juha Auvinen; Bishwajit Bhowmik; Amélie Bonnefond; Fabien Delahaye; Ayse Demirkan; Philippe Froguel; Kadri Haller-Kikkatalo; Hildur Hardardottir; Sandra Hummel; Akhtar Hussain; Eero Kajantie; Elina Keikkala; Amna Khamis; Jari Lahti; Tove Lekva; Sanna Mustaniemi; Christine Sommer; Aili Tagoma; Evangelia Tzala; Raivo Uibo; Marja Vääräsmäki; Pia M Villa; Kåre I Birkeland; Luigi Bouchard; Cornelia M Duijn; Sarah Finer; Leif Groop; Esa Hämäläinen; Geoffrey M Hayes; Graham A Hitman; Hak C Jang; Marjo-Riitta Järvelin; Anne Karen Jenum; Hannele Laivuori; Ronald C Ma; Olle Melander; Emily Oken; Kyong Soo Park; Patrice Perron; Rashmi B Prasad; Elisabeth Qvigstad; Sylvain Sebert; Kari Stefansson; Valgerdur Steinthorsdottir; Tiinamaija Tuomi; Marie-France Hivert; Paul W Franks; Mark I McCarthy; Cecilia M Lindgren; Rachel M Freathy; Deborah A Lawlor; Andrew P Morris; Reedik Mägi

doi:10.1093/hmg/ddac050

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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

Natalia Pervjakova, Gunn-Helen Moen, Maria-Carolina Borges, Teresa Ferreira, James P Cook, Catherine Allard, Robin N Beaumont, Mickaël Canouil, Gad Hatem, Anni Heiskala, …

Human molecular genetics, Vol.31(19), pp.3377-3391

29/09/2022

DOI: https://doi.org/10.1093/hmg/ddac050

PMID: 35220425

Abstract

Diabetes Mellitus, Type 2 - epidemiology

Diabetes Mellitus, Type 2 - genetics

Diabetes, Gestational - genetics

Female

Genetic Predisposition to Disease

Genome-Wide Association Study

Glucose

Humans

Polymorphism, Single Nucleotide - genetics

Pregnancy

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10-54), TCF7L2 (P = 4.0 × 10-16), CDKAL1 (P = 1.6 × 10-14), CDKN2A-CDKN2B (P = 4.1 × 10-9) and HKDC1 (P = 2.9 × 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

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Title: Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes
Creators: Natalia Pervjakova - University of Tartu
Gunn-Helen Moen - University of Oslo
Maria-Carolina Borges - MRC Epidemiology Unit
Teresa Ferreira - Health Data Research UK
James P Cook - University of Liverpool
Catherine Allard - Centre Hospitalier Universitaire de Sherbrooke
Robin N Beaumont - University of Exeter
Mickaël Canouil - European Genomic Institute for Diabetes
Gad Hatem - Skåne University Hospital
Anni Heiskala - University of Oulu
Anni Joensuu - Finnish Institute for Health and Welfare
Ville Karhunen - University of Oulu
Soo Heon Kwak - Seoul National University Hospital
Frederick T J Lin - Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Jun Liu - University of Oxford
Sheryl Rifas-Shiman - Harvard Pilgrim Health Care
Claudia H Tam - Chinese University of Hong Kong
Wing Hung Tam - Chinese University of Hong Kong
Gudmar Thorleifsson - deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
Toby Andrew - European Genomic Institute for Diabetes
Juha Auvinen - University of Oulu
Bishwajit Bhowmik - Centre of Global Health Research, Diabetic Association of Bangladesh, Dhaka, Bangladesh
Amélie Bonnefond - Imperial College London
Fabien Delahaye - European Genomic Institute for Diabetes
Ayse Demirkan - University of Surrey
Philippe Froguel - Imperial College London
Kadri Haller-Kikkatalo - University of Tartu
Hildur Hardardottir - Livio Reykjavik, Reykjavik, Iceland
Sandra Hummel - Helmholtz Zentrum München
Akhtar Hussain - Nord University
Eero Kajantie - Norwegian University of Science and Technology
Elina Keikkala - Finnish Institute for Health and Welfare
Amna Khamis - European Genomic Institute for Diabetes
Jari Lahti - University of Helsinki
Tove Lekva - Oslo University Hospital
Sanna Mustaniemi - Finnish Institute for Health and Welfare
Christine Sommer - Oslo University Hospital
Aili Tagoma - University of Tartu
Evangelia Tzala - Imperial College London
Raivo Uibo - University of Tartu
Marja Vääräsmäki - Finnish Institute for Health and Welfare
Pia M Villa - Helsinki University Hospital
Kåre I Birkeland - Oslo University Hospital
Luigi Bouchard - Université de Sherbrooke
Cornelia M Duijn - University of Oxford
Sarah Finer - Queen Mary University of London
Leif Groop - University of Helsinki
Esa Hämäläinen - University of Eastern Finland
Geoffrey M Hayes - Northwestern University
Graham A Hitman - Queen Mary University of London
Hak C Jang - Seoul National University Bundang Hospital
Marjo-Riitta Järvelin - St Mary's Hospital
Anne Karen Jenum - University of Oslo
Hannele Laivuori - Tampere University Hospital
Ronald C Ma - Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China
Olle Melander - Skåne University Hospital
Emily Oken - Harvard Pilgrim Health Care
Kyong Soo Park - Seoul National University
Patrice Perron - Centre Hospitalier Universitaire de Sherbrooke
Rashmi B Prasad - Skåne University Hospital
Elisabeth Qvigstad - Oslo University Hospital
Sylvain Sebert - University of Oulu
Kari Stefansson - deCODE Genetics
Valgerdur Steinthorsdottir - deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
Tiinamaija Tuomi - Institute for Molecular Medicine Finland
Marie-France Hivert - Massachusetts General Hospital
Paul W Franks - Harvard University
Mark I McCarthy - Wellcome Centre for Human Genetics
Cecilia M Lindgren - University of Oxford
Rachel M Freathy - University of Exeter
Deborah A Lawlor - NIHR
Andrew P Morris - Versus Arthritis
Reedik Mägi - University of Tartu
Publication Details: Human molecular genetics, Vol.31(19), pp.3377-3391
Date published: 29/09/2022
Grant note: MC_UU_00011/6 / Medical Research Council CS/16/4/32482 / British Heart Foundation Wellcome Trust MR/N024397/1 / Medical Research Council R01 HD034568 / NICHD NIH HHS WT088806 / Wellcome UH3 OD023286 / NIH HHS 217065/Z/19/ / UK Medical Research Council and Wellcome
Identifiers: 99828461902346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article
SDG (Scopus 2023): SDG 3

Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

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