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

Pervjakova, Natalia; Moen, Gunn-Helen; Borges, Maria-Carolina; Ferreira, Teresa; Cook, James P.; Allard, Catherine; Beaumont, Robin N.; Canouil, Mickael; Hatem, Gad; Heiskala, Anni; Joensuu, Anni; Karhunen, Ville; Kwak, Soo Heon; Lin, Frederick T. J.; Liu, Jun; Rifas-Shiman, Sheryl; Tam, Claudia H.; Tam, Wing Hung; Thorleifsson, Gudmar; Andrew, Toby; Auvinen, Juha; Bhowmik, Bishwajit; Bonnefond, Amelie; Delahaye, Fabien; Demirkan, Ayse; Froguel, Philippe; Haller-Kikkatalo, Kadri; Hardardottir, Hildur; Hummel, Sandra; Hussain, Akhtar; Kajantie, Eero; Keikkala, Elina; Khamis, Amna; Lahti, Jari; Lekva, Tove; Mustaniemi, Sanna; Sommer, Christine; Tagoma, Aili; Tzala, Evangelia; Uibo, Raivo; Vääräsmäki, Marja; Villa, Pia M.; Birkeland, Kare, I; Bouchard, Luigi; Duijn, Cornelia M.; Finer, Sarah; Groop, Leif; Hamalainen, Esa; Hayes, Geoffrey M.; Hitman, Graham A.; Jang, Hak C.; Järvelin, Marjo-Riitta; Jenum, Anne Karen; Laivuori, Hannele; Ma, Ronald C.; Melander, Olle; Oken, Emily; Park, Kyong Soo; Perron, Patrice; Prasad, Rashmi B.; Qvigstad, Elisabeth; Sebert, Sylvain; Stefansson, Kari; Steinthorsdottir, Valgerdur; Tuomi, Tiinamaija; Hivert, Marie-France; Franks, Paul W.; McCarthy, Mark, I; Lindgren, Cecilia M.; Freathy, Rachel M.; Lawlor, Deborah A.; Morris, Andrew P.; Magi, Reedik (2022-02-26)
 
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https://doi.org/10.1093/hmg/ddac050

Pervjakova, Natalia
Moen, Gunn-Helen
Borges, Maria-Carolina
Ferreira, Teresa
Cook, James P.
Allard, Catherine
Beaumont, Robin N.
Canouil, Mickael
Hatem, Gad
Heiskala, Anni
Joensuu, Anni
Karhunen, Ville
Kwak, Soo Heon
Lin, Frederick T. J.
Liu, Jun
Rifas-Shiman, Sheryl
Tam, Claudia H.
Tam, Wing Hung
Thorleifsson, Gudmar
Andrew, Toby
Auvinen, Juha
Bhowmik, Bishwajit
Bonnefond, Amelie
Delahaye, Fabien
Demirkan, Ayse
Froguel, Philippe
Haller-Kikkatalo, Kadri
Hardardottir, Hildur
Hummel, Sandra
Hussain, Akhtar
Kajantie, Eero
Keikkala, Elina
Khamis, Amna
Lahti, Jari
Lekva, Tove
Mustaniemi, Sanna
Sommer, Christine
Tagoma, Aili
Tzala, Evangelia
Uibo, Raivo
Vääräsmäki, Marja
Villa, Pia M.
Birkeland, Kare, I
Bouchard, Luigi
Duijn, Cornelia M.
Finer, Sarah
Groop, Leif
Hamalainen, Esa
Hayes, Geoffrey M.
Hitman, Graham A.
Jang, Hak C.
Järvelin, Marjo-Riitta
Jenum, Anne Karen
Laivuori, Hannele
Ma, Ronald C.
Melander, Olle
Oken, Emily
Park, Kyong Soo
Perron, Patrice
Prasad, Rashmi B.
Qvigstad, Elisabeth
Sebert, Sylvain
Stefansson, Kari
Steinthorsdottir, Valgerdur
Tuomi, Tiinamaija
Hivert, Marie-France
Franks, Paul W.
McCarthy, Mark, I
Lindgren, Cecilia M.
Freathy, Rachel M.
Lawlor, Deborah A.
Morris, Andrew P.
Magi, Reedik
Oxford University Press
26.02.2022

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, Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes, Human Molecular Genetics, Volume 31, Issue 19, 1 October 2022, Pages 3377–3391, https://doi.org/10.1093/hmg/ddac050

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

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