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

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 AndrewJuha 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

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Abstract

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.

Original language	English
Pages (from-to)	3377-3391
Number of pages	15
Journal	Human Molecular Genetics
Volume	31
Issue number	19
Early online date	26 Feb 2022
DOIs	https://doi.org/10.1093/hmg/ddac050
Publication status	Published - 1 Oct 2022
Publication type	A1 Journal article-refereed

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Publication forum level 2

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://urn.fi/URN:NBN:fi:tuni-202211228534Licence: CC BY

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Pervjakova, N., Moen, G. H., Borges, M. C., Ferreira, T., Cook, J. P., Allard, C., Beaumont, R. N., Canouil, M., Hatem, G., Heiskala, A., Joensuu, A., Karhunen, V., Kwak, S. H., Lin, F. T. J., Liu, J., Rifas-Shiman, S., Tam, C. H., Tam, W. H., Thorleifsson, G., ... Mägi, R. (2022). Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes. Human Molecular Genetics, 31(19), 3377-3391. https://doi.org/10.1093/hmg/ddac050

@article{15b31fa292e34393b8a55420d96cd15b,

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

abstract = "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.",

author = "Natalia Pervjakova and Moen, {Gunn Helen} and Borges, {Maria Carolina} and Teresa Ferreira and Cook, {James P.} and Catherine Allard and Beaumont, {Robin N.} and Micka{\"e}l Canouil and Gad Hatem and Anni Heiskala and Anni Joensuu and Ville Karhunen and Kwak, {Soo Heon} and Lin, {Frederick T.J.} and Jun Liu and Sheryl Rifas-Shiman and Tam, {Claudia H.} and Tam, {Wing Hung} and Gudmar Thorleifsson and Toby Andrew and Juha Auvinen and Bishwajit Bhowmik and Am{\'e}lie Bonnefond and Fabien Delahaye and Ayse Demirkan and Philippe Froguel and Kadri Haller-Kikkatalo and Hildur Hardardottir and Sandra Hummel and Akhtar Hussain and Eero Kajantie and Elina Keikkala and Amna Khamis and Jari Lahti and Tove Lekva and Sanna Mustaniemi and Christine Sommer and Aili Tagoma and Evangelia Tzala and Raivo Uibo and Marja V{\"a}{\"a}r{\"a}sm{\"a}ki and Villa, {Pia M.} and Birkeland, {K{\aa}re I.} and Luigi Bouchard and Duijn, {Cornelia M.} and Sarah Finer and Leif Groop and Esa H{\"a}m{\"a}l{\"a}inen and Hayes, {Geoffrey M.} and Hitman, {Graham A.} and Jang, {Hak C.} and J{\"a}rvelin, {Marjo Riitta} and Jenum, {Anne Karen} and Hannele Laivuori and Ma, {Ronald C.} and Olle Melander and Emily Oken and Park, {Kyong Soo} and Patrice Perron and Prasad, {Rashmi B.} and Elisabeth Qvigstad and Sylvain Sebert and Kari Stefansson and Valgerdur Steinthorsdottir and Tiinamaija Tuomi and Hivert, {Marie France} and Franks, {Paul W.} and McCarthy, {Mark I.} and Lindgren, {Cecilia M.} and Freathy, {Rachel M.} and Lawlor, {Deborah A.} and Morris, {Andrew P.} and Reedik M{\"a}gi",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2022. Published by Oxford University Press.",

year = "2022",

month = oct,

day = "1",

doi = "10.1093/hmg/ddac050",

language = "English",

volume = "31",

pages = "3377--3391",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "19",

}

Pervjakova, N, Moen, GH, Borges, MC, Ferreira, T, Cook, JP, Allard, C, Beaumont, RN, Canouil, M, Hatem, G, Heiskala, A, Joensuu, A, Karhunen, V, Kwak, SH, Lin, FTJ, Liu, J, Rifas-Shiman, S, Tam, CH, Tam, WH, Thorleifsson, G, Andrew, T, Auvinen, J, Bhowmik, B, Bonnefond, A, Delahaye, F, Demirkan, A, Froguel, P, Haller-Kikkatalo, K, Hardardottir, H, Hummel, S, Hussain, A, Kajantie, E, Keikkala, E, Khamis, A, Lahti, J, Lekva, T, Mustaniemi, S, Sommer, C, Tagoma, A, Tzala, E, Uibo, R, Vääräsmäki, M, Villa, PM, Birkeland, KI, Bouchard, L, Duijn, CM, Finer, S, Groop, L, Hämäläinen, E, Hayes, GM, Hitman, GA, Jang, HC, Järvelin, MR, Jenum, AK, Laivuori, H, Ma, RC, Melander, O, Oken, E, Park, KS, Perron, P, Prasad, RB, Qvigstad, E, Sebert, S, Stefansson, K, Steinthorsdottir, V, Tuomi, T, Hivert, MF, Franks, PW, McCarthy, MI, Lindgren, CM, Freathy, RM, Lawlor, DA, Morris, AP & Mägi, R 2022, 'Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes', Human Molecular Genetics, vol. 31, no. 19, pp. 3377-3391. https://doi.org/10.1093/hmg/ddac050

TY - JOUR

T1 - Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

AU - Pervjakova, Natalia

AU - Moen, Gunn Helen

AU - Borges, Maria Carolina

AU - Ferreira, Teresa

AU - Cook, James P.

AU - Allard, Catherine

AU - Beaumont, Robin N.

AU - Canouil, Mickaël

AU - Hatem, Gad

AU - Heiskala, Anni

AU - Joensuu, Anni

AU - Karhunen, Ville

AU - Kwak, Soo Heon

AU - Lin, Frederick T.J.

AU - Liu, Jun

AU - Rifas-Shiman, Sheryl

AU - Tam, Claudia H.

AU - Tam, Wing Hung

AU - Thorleifsson, Gudmar

AU - Andrew, Toby

AU - Auvinen, Juha

AU - Bhowmik, Bishwajit

AU - Bonnefond, Amélie

AU - Delahaye, Fabien

AU - Demirkan, Ayse

AU - Froguel, Philippe

AU - Haller-Kikkatalo, Kadri

AU - Hardardottir, Hildur

AU - Hummel, Sandra

AU - Hussain, Akhtar

AU - Kajantie, Eero

AU - Keikkala, Elina

AU - Khamis, Amna

AU - Lahti, Jari

AU - Lekva, Tove

AU - Mustaniemi, Sanna

AU - Sommer, Christine

AU - Tagoma, Aili

AU - Tzala, Evangelia

AU - Uibo, Raivo

AU - Vääräsmäki, Marja

AU - Villa, Pia M.

AU - Birkeland, Kåre I.

AU - Bouchard, Luigi

AU - Duijn, Cornelia M.

AU - Finer, Sarah

AU - Groop, Leif

AU - Hämäläinen, Esa

AU - Hayes, Geoffrey M.

AU - Hitman, Graham A.

AU - Jang, Hak C.

AU - Järvelin, Marjo Riitta

AU - Jenum, Anne Karen

AU - Laivuori, Hannele

AU - Ma, Ronald C.

AU - Melander, Olle

AU - Oken, Emily

AU - Park, Kyong Soo

AU - Perron, Patrice

AU - Prasad, Rashmi B.

AU - Qvigstad, Elisabeth

AU - Sebert, Sylvain

AU - Stefansson, Kari

AU - Steinthorsdottir, Valgerdur

AU - Tuomi, Tiinamaija

AU - Hivert, Marie France

AU - Franks, Paul W.

AU - McCarthy, Mark I.

AU - Lindgren, Cecilia M.

AU - Freathy, Rachel M.

AU - Lawlor, Deborah A.

AU - Morris, Andrew P.

AU - Mägi, Reedik

PY - 2022/10/1

Y1 - 2022/10/1

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddac050

DO - 10.1093/hmg/ddac050

M3 - Article

C2 - 35220425

AN - SCOPUS:85133653659

SN - 0964-6906

VL - 31

SP - 3377

EP - 3391

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 19

ER -

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

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