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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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| Author: | Pervjakova, Natalia1; Moen, Gunn-Helen2,3,4,5; Borges, Maria-Carolina5,6; |
| Organizations: |
1Univ Tartu, Estonian Genome Ctr, Inst Genom, EE-51010 Tartu, Estonia. 2Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway. 3Univ Queensland, Diamantina Inst, Woolloongabba, Qld 4102, Australia.
4Norwegian Univ Sci & Technol, KG Jebsen Ctr Genet Epidemiol, Dept Publ Hlth & Nursing, NTNU, Trondheim, Norway.
5Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England. 6Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England. 7Univ Oxford, Li Ka Shing Ctr Hlth Hlth Informat & Discovery, Big Data Inst, Oxford, England. 8Univ Liverpool, Dept Hlth Data Sci, Liverpool, Merseyside, England. 9Univ Sherbrooke, Ctr Rech Ctr Hosp Univ Sherbrooke CRCHUS, Sherbrooke, PQ, Canada. 10Univ Exeter, Coll Med & Hlth, Inst Biomed & Clin Sci, Exeter, Devon, England. 11Inst Pasteur, European Genom Inst Diabet, Inserm U1283, CNRS UMR 8199, F-59000 Lille, France. 12Univ Lille, Lille Univ Hosp, F-59000 Lille, France. 13Lund Univ, Skane Univ Hosp, Lund Univ Diabet Ctr, Dept Clin Sci, SE-20502 Malmo, Sweden. 14Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu, Finland. 15Finnish Inst Hlth & Welf, Dept Publ Hlth Solut, Helsinki, Finland. 16Univ Helsinki, Fac Med, Res Program Clin & Mol Metab, Helsinki, Finland. 17Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, St Marys Hosp, London, England. 18Seoul Natl Univ Hosp, Dept Internal Med, Seoul, South Korea. 19Northwestern Univ, Dept Med, Div Endocrinol Metab & Mol Med, Feinberg Sch Med, Chicago, IL 60611 USA. 20Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. 21Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England. 22Harvard Med Sch, Dept Populat Med, Boston, MA 02115 USA. 23Harvard Pilgrim Hlth Care Inst, Boston, MA USA. 24Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Peoples R China. 25Chinese Univ Hong Kong, Dept Obstet & Gynaecol, Hong Kong, Peoples R China. 26Amgen Inc, DeCODE Genet, Reykjavik, Iceland. 27Imperial Coll London, Dept Metab Digest & Reprod, London, England. 28Diabet Assoc Bangladesh, Ctr Global Hlth Res, Dhaka, Bangladesh. 29Univ Surrey, Dept Clin & Expt Res, Sect Stat Multiomics, Guildford, Surrey, England. 30Univ Tartu, Inst Biomed & Translat Med, Dept Immunol, Tartu, Estonia. 31Univ Iceland, Fac Med, Reykjavik, Iceland. 32Livio Reykjavik, Reykjavik, Iceland. 33Helmholtz Zentrum Munchen, Inst Diabet Res, German Res Ctr Environm Hlth, Munich, Germany. 34Tech Univ Munich, Klinikum Rechts Isar, Forschergrp Diabet, Munich, Germany. 35Nord Univ, Fac Hlth Sci, Bodo, Norway. 36Finnish Inst Hlth & Welf, Populat Hlth Unit, Helsinki, Finland. 37Finnish Inst Hlth & Welf, Populat Hlth Unit, Oulu, Finland. 38Oulu Univ Hosp, PEDEGO Res Unit, MRC Oulu, Oulu, Finland. 39Univ Oulu, Oulu, Finland. 40Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway. 41Univ Helsinki, Dept Psychol & Logoped, Helsinki, Finland. 42Oslo Univ Hosp, Res Inst Internal Med, Oslo, Norway. 43Oslo Univ Hosp, Dept Endocrinol Morbid Obes & Prevent Med, Oslo, Norway. 44Univ Helsinki, Dept Obstet & Gynaecol, Helsinki, Finland. 45Helsinki Univ Hosp, Helsinki, Finland. 46Helsinki & Uusimaa Hosp Dist, Hyvink Hosp, Hyvinkaa, Finland. 47Oslo Univ Hosp, Dept Transplantat Med, Oslo, Norway. 48Univ Sherbrooke, Fac Med & Hlth Sci, Dept Biochem & Funct Genom, Sherbrooke, PQ, Canada. 49Hop Chicoutimi, Dept Med Biol, Ctr Integre Univ Sante & Serv Sociaux Saguenay La, Chicoutimi, PQ, Canada. 50Queen Mary Univ London, Ctr Genom & Child Hlth, Barts & London Sch Med & Dent, Blizard Inst, London, England. 51Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki Inst Life Sci, Helsinki, Finland. 52Univ Eastern Finland, Dept Clin Chem, Kuopio, Finland. 53Northwestern Univ, Ctr Genet Med, Feinberg Sch Med, Chicago, IL 60611 USA. 54Northwestern Univ, Dept Anthropol, Evanston, IL 60208 USA. 55Seoul Natl Univ, Dept Internal Med, Bundang Hosp, Seongnam, South Korea. 56Seoul Natl Univ, Dept Internal Med, Coll Med, Seoul, South Korea. 57Univ Oslo, Fac Med, Inst Hlth & Soc, Dept Gen Practice,Gen Practice Res Unit AFE, Post Box 1130 Blindern, N-0318 Oslo, Norway. 58Tampere Univ, Tampere Univ Hosp, Dept Obstet & Gynecol, Tampere, Finland. 59Tampere Univ, Ctr Child Adolescent & Maternal Hlth, Fac Med & Hlth Technol, Tampere, Finland. 60Univ Helsinki, Med & Clin Genet, Helsinki, Finland. 61Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Lab Mol Epidemiol Diabet, Hong Kong, Peoples R China. 62Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Peoples R China. 63Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, Seoul, South Korea. 64Univ Sherbrook, Fac Med & Hlth Sci, Dept Med, Sherbrooke, PQ, Canada. 65Helsinki Univ Hosp, Abdominal Ctr, Dept Endocrinol, Helsinki, Finland. 66Folkhalsan Res Ctr, Helsinki, Finland. 67Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. 68Lund Univ, Dept Clin Sci, Malmo, Sweden. 69Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. 70Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Radcliffe Dept Med, Oxford, England. 71Univ Oxford, Wellcome Ctr Human Genet, Nuffield Dept Med, Oxford, England. 72Broad Inst, Program Med & Populat Genet, Boston, MA USA. 73Bristol NIHR Biomed Res Ctr, Bristol, Avon, England. 74Univ Manchester, Ctr Genet & Genom Versus Arthrit, Ctr Musculoskeletal Res, Div Musculoskeletal & Dermatol Sci, Manchester, Lancs, England. |
| Format: | article |
| Version: | published version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 0.8 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe2022080953402 |
| Language: | English |
| Published: |
Oxford University Press,
2022
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| Publish Date: | 2022-08-09 |
| Description: |
AbstractGestational 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 x 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 x 10-54), TCF7L2 (P = 4.0 x 10-16), CDKAL1 (P = 1.6 x 10-14), CDKN2A-CDKN2B (P = 4.1 x 10-9) and HKDC1 (P = 2.9 x 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. see all
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| Series: |
Human molecular genetics |
| ISSN: | 0964-6906 |
| ISSN-E: | 1460-2083 |
| ISSN-L: | 0964-6906 |
| Volume: | 31 |
| Issue: | 19 |
| Pages: | 3377 - 3391 |
| DOI: | 10.1093/hmg/ddac050 |
| OADOI: | https://oadoi.org/10.1093/hmg/ddac050 |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3123 Gynaecology and paediatrics |
| Subjects: | |
| Funding: |
ALSPAC. Core funding for ALSPAC is provided by the UK Medical Research Council and Wellcome (217065/Z/19/) and the University of Bristol. Genotyping of the ALSPAC maternal samples was funded by Wellcome (WT088806) and the offspring samples were genotyped by Sample Logistics and Genotyping Facilities at the Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). We are extremely grateful to all the families who took part in ALSPAC, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.
AM. We thank the participants of the ANDIS-MDC study. The study is supported by Swedish Research Council (project grant 521-2010-3490 and infrastructure grants 2010-5983, 2012-5538 and 2014-6395). The study is supported by Crafoord foundation (project grant 20200891) and Hjärt-Lungfonden (project grant: 20180522).
BIB. Born in Bradford (BiB) data used in this research was funded by Wellcome (WT101597MA), a joint grant from the UK Medical Research Council (MRC) and UK Economic and Social Science Research Council (ESRC) (MR/N024397/1), the British Heart Foundation (CS/16/4/32482) and the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber and the Clinical Research Network (CRN). BiB is only possible because of the enthusiasm and commitment of the Children and Parents in BiB. We are grateful to all the participants, teachers, school staff, health professionals and researchers who have made Born in Bradford happen.
BOTNIA. The Botnia Study (L.G., T.T.) have been financially supported by grants from Folkhälsan Research Foundation, the Sigrid Juselius Foundation, The Academy of Finland (grant nos 263401, 267882, 312063, 336822 to L.G.; 312072 and 336826 to T.T.), University of Helsinki, Nordic Center of Excellence in Disease Genetics, EU (EXGENESIS), MOSAIC FP7-600914, Ollqvist Foundation, Swedish Cultural Foundation in Finland, Finnish Diabetes Research Foundation, Foundation for Life and Health in Finland, Signe and Ane Gyllenberg Foundation, Finnish Medical Society, Paavo Nurmi Foundation, State Research Funding via the Helsinki University Hospital, Perklén Foundation, Närpes Health Care Foundation and Ahokas Foundation. The study has also been supported by the Ministry of Education in Finland, Municipal Heath Care Center and Hospital in Jakobstad and Health Care Centers in Vasa, Närpes and Korsholm. The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement (n° 269045). The study is also supported by Crafoord foundation (project grant 20200891) and Hjärt-Lungfonden (project grant: 20180522) (R.B.P.). The skilful assistance of the Botnia Study Group is gratefully acknowledged.
DECODE. We thank the women who have participated in the deCODE study.
EstBB. This study was funded by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012 and Project No. 2014-2020.4.01.16-0125); by the European Union through Horizon 2020 research and innovation programme under grant agreement (No. 101017802 and 810645); and by the Estonian Research Council grants PUT (PRG687, PRG1291). Data analyses were carried out in part in the High-Performance Computing Center of University of Tartu. We thank participants and support staff of Estonian Biobank.
FINNGEDI. The EPx-GDM study has been supported by the French government, managed by the National Research Agency (ANR) under the Future Investment Program (PIA) with the references ANR-10-LABX-0046 (European Genomic Institute for Diabetes [E.G.I.D]) and ANR-10-EQPX-07-01 (LIGAN-PM). This work was also supported by the ANR-16-CE17-0017-01, by the Fondation Francophone pour la Recherche sur le Diabète (FFRD) that is sponsored by the Fédération Française des Diabétiques (FFD), Abbott, AstraZeneca, Eli Lilly, Merck Sharp & Dohme (MSD) and Novo Nordisk, and by the National Center for Precision Diabetic Medicine—PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council and by the European Metropolis of Lille (MEL). The FinnGeDi study was supported by: Academy of Finland, Diabetes Research Foundation, Foundation for Pediatric Research, Juho Vainio Foundation, Novo Nordisk Foundation, Signe and Ane Gyllenberg Foundation, Sigrid Jusélius Foundation, Yrjö Jahnsson Foundation for Pediatric Research, Finnish Diabetes Medical Foundation, Research Funds of Oulu University Hospital (state grants), Research Foundation, Novo Nordisk Foundation, funds of Helsinki University Hospital (state grants), Medical Research Center Oulu and National Institute for Health and Welfare (Finland).
ERF. We are grateful to all participants and their relatives, to general practitioners and neurologists for their contributions, to P. Veraart for her help in genealogy, to Jeannette Vergeer for the supervision of the laboratory work and to P. Snijders for his help in data collection. The ERF study was supported by grants from the Netherlands Organisation for Scientific Research (Pionier, 047.016.009, 047.017.043), Erasmus MC and the Centre for Medical Systems Biology (CMSB; National Genomics Initiative). Ayse Demrkan was supported by NWO (VENI-91616165), WCRF-2017/1641 and H2020-SC1-2019-874739.
ESTGDM. This study was supported by the Estonian Research Council grants (IUT20-43 and PRG712). We are grateful to Dr Anne Kirss and midwife Mrs Laura Lauren from Women’s Clinic, Tartu University Hospital, for interviewing the participants and collecting the blood samples.
GEN3G. Gen3G has been supported by an American Diabetes Association accelerator award #1-15-ACE-26 (M.F.H); Fonds de Recherche du Québec en Santé #20697 (M.F.H.); Canadian Institute of Health Research #MOP 115071 (M.F.H.) and Diabète Québec grants (P.P. and L.B.). Gen3G research team thanks all Gen3G participants.
GIFTS. This study was supported by Medical Research Council [Clinical Research Training Fellowship (G0800441)], the European Union (FP7 EU grant: 83599025) and the Diabetes Association of Bangladesh. The authors are indebted to all the participants from Dhaka (Bangladesh) and London (UK).
HONGKONG. The work for CUHK GDM cohort was supported by the Research Grants Council General Research Fund (CUHK 473408, CUHK 471713, 14118718). We also acknowledge support from the RGC Theme-based Research Scheme (T12-402/13 N) and Research Impact Fund (R4012-18), the Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Fund and the Croucher Foundation Senior Medical Research Fellowship.
NFBC Cohort 1966 31y follow-up study. We thank all cohort members and researchers who participated in the 31 years study. We also wish acknowledge the work of the NFBC project centre. NFBC1966 received financial support from University of Oulu (Grant nos 65354 and 24000692); Oulu University Hospital (Grant nos 2/97, 8/97 and 24301140); Ministry of Health and Social Affairs (Grant nos 23/251/97, 160/97, 190/97). National Institute for Health and Welfare, Helsinki (Grant no. 54121); Regional Institute of Occupational Health, Oulu, Finland (Grant nos 50621, 54231, 54121); Regional Institute of Occupational Health, Oulu, Finland (Grant no. 50621, 54231); and ERDF European Regional Development Fund (Grant no. 539/2010 A31592). The NFBC team is acknowledging the following Funding/Support: This work was supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement (No. 633595) (DynaHEALTH) and grant agreement No.733206 (LifeCycle) H2020-824989 EUCANCONNECT, H2020-873749 LongITools, H2020-848158 EarlyCause and the JPI HDHL, PREcisE project MR/S03658X/1, ZonMw the Netherlands (no. P75416); the academy of Finland EGEA-project (285547).
NFBC Cohort 1966 46y follow-up study. We thank all cohort members and researchers who participated in the 46 years study. We also wish acknowledge the work of the NFBC project centre. NFBC1966 received financial support from University of Oulu (Grant no. 24000692); Oulu University Hospital (Grant no. 24301140); ERDF European Regional Development Fund (Grant no. 539/2010 A31592).
NFBC Cohort 1986. We thank all cohort members and researchers who have participated in the study. We also wish acknowledge the work of the NFBC project centre.
NFBC1986 received financial support: EU QLG1-CT-2000-01643 (EUROBLCS) (Grant no. E51560); NorFA (Grant no. 731, 20056, 30167); USA/NIH 2000 G DF682 (Grant no. 50945). The NFBC team acknowledges the following funding/support: the European Union’s Horizon 2020 research and innovation programme under grant agreement (No. 633595) (DynaHEALTH) and grant agreement (No.733206) (LifeCycle) H2020-824989 EUCANCONNECT, H2020-873749 LongITools, H2020-848158 EarlyCause and the JPI HDHL, PREcisE project, ZonMw the Netherlands (no. P75416); the academy of Finland EGEA-project (285547).
PREDO. The PREDO study was supported by Academy of Finland, EVO research funding (A special Finnish state subsidy for health science research), Finnish Medical Foundation, Jane and Aatos Erkko Foundation, Päivikki and Sakari Sohlberg Foundation, University of Helsinki Research Funding, Jalmari ja Rauha Ahokas Foundation, Yrjö Jahnsson Foundation and Juho Vainio Foundation.
SNUH. This work was supported by the Korea Health 21 R&D Project, Korean Ministry of Health and Welfare (grant no. 00-PJ3-PG6-GN07-001). This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea to S.H.K. (grant number HI15C3131).
STORK. The STORK study received additional funding from the Norwegian Diabetes Association, the Norwegian Odd Fellow Research Fund and Johan Selmer Kvanes’ Endowment for Research in Diabetes.
STORKG. Acknowledge Hormone Laboratory, Oslo University Hospital for DNA-extraction.
UKBB. UK Biobank analyses were conducted using the UK Biobank resource under application 11867.
VIVA. Grants from the US National Institutes of Health (R01 HD034568, UH3 OD023286). Project Viva is thankful to all Project Viva participants for their participation to research over many years.
Individual author acknowledgements. D.A.L. is supported by the European Research Council (669545); US National Institute for Health (R01 DK10324) and British Heart Foundation (CH/F/20/90003). D.A.L. and M.C.B. work in a Unit supported by the University of Bristol and the UK Medical Research Council (MC_UU_00011/6) and are supported by a British Heart Foundation Accelerator Award (AA/18/7/34219). R.M.F. and R.N.B. were supported by Sir Henry Dale Fellowship (Wellcome and Royal Society grant: WT104150). R.M.F. is funded by a Wellcome Senior Research Fellowship (WT220390). G.H.M. has received funding from the South-Eastern Health Authority of Norway, the Norwegian Diabetes Association and Nils Normans Minnegave. G.H.M. is supported by the Norwegian Research Council (Post doctorial mobility research grant 287198).
M.C.B. was funded by a Medical Research Council (MRC) Skills Development Fellowship [MR/P014054/1] and a University of Bristol Vice-Chancellor’s Fellowship.
The authors acknowledge the use of the University of Exeter High-Performance Computing (HPC) facility in carrying out this work.
Funders and others acknowledged here had no influence on the study design, data collection or interpretation of results. Views expressed are those of the authors and not necessarily any funder or other acknowledged here.
This research was funded in part by Wellcome grants (WT104150 and WT220390). A CC BY or equivalent licence is applied to the author accepted manuscript arising from this submission, in accordance with the grant’s open access conditions.
Conflicts of Interest statement. D.A.L. has received support from Roche Diagnostics and Medtronic Ltd for work unrelated to that presented here. M.I.M. has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier and Takeda. M.I.M. is now an employee of Genentech and a holder of Roche stock. G.T., V.S. and K.S. are employees of deCODE genetics/Amgen, Inc. |
| EU Grant Number: |
(633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging (733206) LIFECYCLE - Early-life stressors and LifeCycle health (824989) EUCAN-Connect - A federated FAIR platform enabling large-scale analysis of high-value cohort data connecting Europe and Canada in personalized health (874739) LONGITOOLS - Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases (848158) EarlyCause - Causative mechanisms & integrative models linking early-life-stress to psycho-cardio-metabolic multi-morbidity (640887) LTCeramics - Low Temperature Ceramics Applications |
| Academy of Finland Grant Number: |
285547 |
| Detailed Information: |
285547 (Academy of Finland Funding decision) |
| Dataset Reference: |
Meta-analysis summary statistics can be downloaded from: https://tools.gi.ut.ee/tools/GENDIP_PervjakovaEtAl2022.txt.gz. |
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https://tools.gi.ut.ee/tools/GENDIP_PervjakovaEtAl2022.txt.gz |
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| Copyright information: |
© The Author(s) 2022. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
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https://creativecommons.org/licenses/by/4.0/ |