Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects

Caroline Brito Nunes; Valentina Rukins; Aminata H. Cisse; Frédérique White; Nancy McBride; Alan Kuang; Catherine Allard; Justiina Ronkainen; Alice Hughes; Amanda Elliott; Gudmar Thorleifsson; Marc Vaudel; Triin Laisk; Yuqin Gu; Amel Lamri; Li Chen; Johanna Tuhkanen; Jari Lahti; Lucinda Calas; Manon Muntaner; Ville Karhunen; Jaewon Choi; Anni Heiskala; Gad Hatem; Nicolas Fragoso-Bargas; Sheryl L. Rifas-Shiman; Guillermo Paz-Lopez; Sara E. Stinson; Bishwajit Bhowmik; Emma Ahlqvist; Jean-Francois Deleuze; Johan G. Eriksson; Jongseok Park; Koon Teo; Katri Räikkönen; Kari Stefansson; Maria Molina-Vega; Padmaja Subbarao; Robin N. Beaumont; Stefan Johansson; Tiinamaija Tuomi; Torben Hansen; Line Engelbrechtsen; Sonsoles Morcillo; Emily Oken; Elisabeth Quigstad; Kåre I. Birkeland; Marja Vääräsmäki; Andrew T. Hattersley; Sylvain Sebert; Graham A Hitman; Soo Heon Kwak; Marjo-Riitta Järvelin; Rashmi B Prasad; Barbara Heude; Aline Meirhaeghe; Luigi Bouchard; Pierre-Étienne Jacques; Hannele Laivuori; Kok Hian Tan; Sonia S. Anand; David A. van Heel; Siyang Liu; Pål R. Njølstad; Valgerdur Steinthorsdottir; Elisabeth Widén; Elina Keikkala; Denise M Scholtens; William L. Lowe; Sarah Finer; Andrew P Morris; Reedik Mägi; Julia Zöllner; Maria Carolina Borges; Deborah A. Lawlor; Marie-France Hivert; Rachel M. Freathy; David M Evans; Gunn-Helen Moen

doi:10.1101/2025.08.19.25333735

Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects

Caroline Brito Nunes^*, Valentina Rukins, Aminata H. Cisse, Frédérique White, Nancy McBride, Alan Kuang, Catherine Allard, Justiina Ronkainen, Alice Hughes, Amanda Elliott, Gudmar Thorleifsson, Marc Vaudel, Triin Laisk, Yuqin Gu, Amel Lamri, Li Chen, Johanna Tuhkanen, Jari Lahti, Lucinda Calas, Manon MuntanerVille Karhunen, Jaewon Choi, Anni Heiskala, Gad Hatem, Nicolas Fragoso-Bargas, Sheryl L. Rifas-Shiman, Guillermo Paz-Lopez, Sara E. Stinson, Bishwajit Bhowmik, Emma Ahlqvist, Jean-Francois Deleuze, Johan G. Eriksson, Jongseok Park, Koon Teo, Katri Räikkönen, Kari Stefansson, Maria Molina-Vega, Padmaja Subbarao, Robin N. Beaumont, Stefan Johansson, Tiinamaija Tuomi, Torben Hansen, Line Engelbrechtsen, Sonsoles Morcillo, Emily Oken, Elisabeth Quigstad, Kåre I. Birkeland, Marja Vääräsmäki, Andrew T. Hattersley, Sylvain Sebert, Graham A Hitman, Soo Heon Kwak, Marjo-Riitta Järvelin, Rashmi B Prasad, Barbara Heude, Aline Meirhaeghe, Luigi Bouchard, Pierre-Étienne Jacques, Hannele Laivuori, Kok Hian Tan, Sonia S. Anand, David A. van Heel, Siyang Liu, Pål R. Njølstad, Valgerdur Steinthorsdottir, Elisabeth Widén, Elina Keikkala, Denise M Scholtens, William L. Lowe, Sarah Finer, Andrew P Morris, Reedik Mägi, Julia Zöllner, Maria Carolina Borges, Deborah A. Lawlor, Marie-France Hivert, Rachel M. Freathy, David M Evans, Gunn-Helen Moen^*

^*Corresponding author for this work

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Abstract

Gestational diabetes mellitus (GDM) affects ∼14% of pregnancies and is linked to adverse pregnancy outcomes and increased maternal type 2 diabetes mellitus (T2DM) risk. The GenDiP Consortium conducted trans-generational, multi-ancestry genome-wide association study meta-analyses of GDM and pregnancy glycemic traits in up to 38,305 GDM cases and 776,145 controls. We identified 37 GDM-associated loci (19 novel) and five novel loci for glycemic traits, all operating through the maternal genome. Most GDM loci overlapped with T2DM and non-pregnant glycemic traits, with limited evidence for pregnancy-specific effects. MTNR1B showed pregnancy-enhanced effects on 2-hour glucose, potentially mediated by interaction with GPR61, a novel GDM locus, suggesting a gestation-specific melatonin-glucose signalling axis. We also observed ancestry-specific effects at the fasting glucose locus ABCB11, with opposite directions in European and East Asian populations. Our findings provide new insights into the genetic architecture of GDM and highlight the need for larger, ancestrally diverse studies.

Original language	English
Publisher	medRxiv
Number of pages	46
DOIs	https://doi.org/10.1101/2025.08.19.25333735
Publication status	Accepted/In press - 21 Aug 2025

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Brito Nunes, C., Rukins, V., Cisse, A. H., White, F., McBride, N., Kuang, A., Allard, C., Ronkainen, J., Hughes, A., Elliott, A., Thorleifsson, G., Vaudel, M., Laisk, T., Gu, Y., Lamri, A., Chen, L., Tuhkanen, J., Lahti, J., Calas, L., ... Moen, G.-H. (Accepted/In press). Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects. medRxiv. https://doi.org/10.1101/2025.08.19.25333735

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title = "Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects",

abstract = "Gestational diabetes mellitus (GDM) affects ∼14\% of pregnancies and is linked to adverse pregnancy outcomes and increased maternal type 2 diabetes mellitus (T2DM) risk. The GenDiP Consortium conducted trans-generational, multi-ancestry genome-wide association study meta-analyses of GDM and pregnancy glycemic traits in up to 38,305 GDM cases and 776,145 controls. We identified 37 GDM-associated loci (19 novel) and five novel loci for glycemic traits, all operating through the maternal genome. Most GDM loci overlapped with T2DM and non-pregnant glycemic traits, with limited evidence for pregnancy-specific effects. MTNR1B showed pregnancy-enhanced effects on 2-hour glucose, potentially mediated by interaction with GPR61, a novel GDM locus, suggesting a gestation-specific melatonin-glucose signalling axis. We also observed ancestry-specific effects at the fasting glucose locus ABCB11, with opposite directions in European and East Asian populations. Our findings provide new insights into the genetic architecture of GDM and highlight the need for larger, ancestrally diverse studies.",

author = "\{Brito Nunes\}, Caroline and Valentina Rukins and Cisse, \{Aminata H.\} and Fr{\'e}d{\'e}rique White and Nancy McBride and Alan Kuang and Catherine Allard and Justiina Ronkainen and Alice Hughes and Amanda Elliott and Gudmar Thorleifsson and Marc Vaudel and Triin Laisk and Yuqin Gu and Amel Lamri and Li Chen and Johanna Tuhkanen and Jari Lahti and Lucinda Calas and Manon Muntaner and Ville Karhunen and Jaewon Choi and Anni Heiskala and Gad Hatem and Nicolas Fragoso-Bargas and Rifas-Shiman, \{Sheryl L.\} and Guillermo Paz-Lopez and Stinson, \{Sara E.\} and Bishwajit Bhowmik and Emma Ahlqvist and Jean-Francois Deleuze and Eriksson, \{Johan G.\} and Jongseok Park and Koon Teo and Katri R{\"a}ikk{\"o}nen and Kari Stefansson and Maria Molina-Vega and Padmaja Subbarao and Beaumont, \{Robin N.\} and Stefan Johansson and Tiinamaija Tuomi and Torben Hansen and Line Engelbrechtsen and Sonsoles Morcillo and Emily Oken and Elisabeth Quigstad and Birkeland, \{K{\aa}re I.\} and Marja V{\"a}{\"a}r{\"a}sm{\"a}ki and Hattersley, \{Andrew T.\} and Sylvain Sebert and Hitman, \{Graham A\} and Kwak, \{Soo Heon\} and Marjo-Riitta J{\"a}rvelin and Prasad, \{Rashmi B\} and Barbara Heude and Aline Meirhaeghe and Luigi Bouchard and Pierre-{\'E}tienne Jacques and Hannele Laivuori and Tan, \{Kok Hian\} and Anand, \{Sonia S.\} and \{van Heel\}, \{David A.\} and Siyang Liu and Nj{\o}lstad, \{P{\aa}l R.\} and Valgerdur Steinthorsdottir and Elisabeth Wid{\'e}n and Elina Keikkala and Scholtens, \{Denise M\} and Lowe, \{William L.\} and Sarah Finer and Morris, \{Andrew P\} and Reedik M{\"a}gi and Julia Z{\"o}llner and Borges, \{Maria Carolina\} and Lawlor, \{Deborah A.\} and Marie-France Hivert and Freathy, \{Rachel M.\} and Evans, \{David M\} and Gunn-Helen Moen",

year = "2025",

month = aug,

day = "21",

doi = "10.1101/2025.08.19.25333735",

language = "English",

publisher = "medRxiv",

type = "WorkingPaper",

institution = "medRxiv",

}

Brito Nunes, C, Rukins, V, Cisse, AH, White, F, McBride, N, Kuang, A, Allard, C, Ronkainen, J, Hughes, A, Elliott, A, Thorleifsson, G, Vaudel, M, Laisk, T, Gu, Y, Lamri, A, Chen, L, Tuhkanen, J, Lahti, J, Calas, L, Muntaner, M, Karhunen, V, Choi, J, Heiskala, A, Hatem, G, Fragoso-Bargas, N, Rifas-Shiman, SL, Paz-Lopez, G, Stinson, SE, Bhowmik, B, Ahlqvist, E, Deleuze, J-F, Eriksson, JG, Park, J, Teo, K, Räikkönen, K, Stefansson, K, Molina-Vega, M, Subbarao, P, Beaumont, RN, Johansson, S, Tuomi, T, Hansen, T, Engelbrechtsen, L, Morcillo, S, Oken, E, Quigstad, E, Birkeland, KI, Vääräsmäki, M, Hattersley, AT, Sebert, S, Hitman, GA, Kwak, SH, Järvelin, M-R, Prasad, RB, Heude, B, Meirhaeghe, A, Bouchard, L, Jacques, P-É, Laivuori, H, Tan, KH, Anand, SS, van Heel, DA, Liu, S, Njølstad, PR, Steinthorsdottir, V, Widén, E, Keikkala, E, Scholtens, DM, Lowe, WL, Finer, S, Morris, AP, Mägi, R, Zöllner, J, Borges, MC , Lawlor, DA, Hivert, M-F, Freathy, RM, Evans, DM & Moen, G-H 2025 'Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects' medRxiv. https://doi.org/10.1101/2025.08.19.25333735

TY - UNPB

T1 - Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects

AU - Brito Nunes, Caroline

AU - Rukins, Valentina

AU - Cisse, Aminata H.

AU - White, Frédérique

AU - McBride, Nancy

AU - Kuang, Alan

AU - Allard, Catherine

AU - Ronkainen, Justiina

AU - Hughes, Alice

AU - Elliott, Amanda

AU - Thorleifsson, Gudmar

AU - Vaudel, Marc

AU - Laisk, Triin

AU - Gu, Yuqin

AU - Lamri, Amel

AU - Chen, Li

AU - Tuhkanen, Johanna

AU - Lahti, Jari

AU - Calas, Lucinda

AU - Muntaner, Manon

AU - Karhunen, Ville

AU - Choi, Jaewon

AU - Heiskala, Anni

AU - Hatem, Gad

AU - Fragoso-Bargas, Nicolas

AU - Rifas-Shiman, Sheryl L.

AU - Paz-Lopez, Guillermo

AU - Stinson, Sara E.

AU - Bhowmik, Bishwajit

AU - Ahlqvist, Emma

AU - Deleuze, Jean-Francois

AU - Eriksson, Johan G.

AU - Park, Jongseok

AU - Teo, Koon

AU - Räikkönen, Katri

AU - Stefansson, Kari

AU - Molina-Vega, Maria

AU - Subbarao, Padmaja

AU - Beaumont, Robin N.

AU - Johansson, Stefan

AU - Tuomi, Tiinamaija

AU - Hansen, Torben

AU - Engelbrechtsen, Line

AU - Morcillo, Sonsoles

AU - Oken, Emily

AU - Quigstad, Elisabeth

AU - Birkeland, Kåre I.

AU - Vääräsmäki, Marja

AU - Hattersley, Andrew T.

AU - Sebert, Sylvain

AU - Hitman, Graham A

AU - Kwak, Soo Heon

AU - Järvelin, Marjo-Riitta

AU - Prasad, Rashmi B

AU - Heude, Barbara

AU - Meirhaeghe, Aline

AU - Bouchard, Luigi

AU - Jacques, Pierre-Étienne

AU - Laivuori, Hannele

AU - Tan, Kok Hian

AU - Anand, Sonia S.

AU - van Heel, David A.

AU - Liu, Siyang

AU - Njølstad, Pål R.

AU - Steinthorsdottir, Valgerdur

AU - Widén, Elisabeth

AU - Keikkala, Elina

AU - Scholtens, Denise M

AU - Lowe, William L.

AU - Finer, Sarah

AU - Morris, Andrew P

AU - Mägi, Reedik

AU - Zöllner, Julia

AU - Borges, Maria Carolina

AU - Lawlor, Deborah A.

AU - Hivert, Marie-France

AU - Freathy, Rachel M.

AU - Evans, David M

AU - Moen, Gunn-Helen

PY - 2025/8/21

Y1 - 2025/8/21

N2 - Gestational diabetes mellitus (GDM) affects ∼14% of pregnancies and is linked to adverse pregnancy outcomes and increased maternal type 2 diabetes mellitus (T2DM) risk. The GenDiP Consortium conducted trans-generational, multi-ancestry genome-wide association study meta-analyses of GDM and pregnancy glycemic traits in up to 38,305 GDM cases and 776,145 controls. We identified 37 GDM-associated loci (19 novel) and five novel loci for glycemic traits, all operating through the maternal genome. Most GDM loci overlapped with T2DM and non-pregnant glycemic traits, with limited evidence for pregnancy-specific effects. MTNR1B showed pregnancy-enhanced effects on 2-hour glucose, potentially mediated by interaction with GPR61, a novel GDM locus, suggesting a gestation-specific melatonin-glucose signalling axis. We also observed ancestry-specific effects at the fasting glucose locus ABCB11, with opposite directions in European and East Asian populations. Our findings provide new insights into the genetic architecture of GDM and highlight the need for larger, ancestrally diverse studies.

AB - Gestational diabetes mellitus (GDM) affects ∼14% of pregnancies and is linked to adverse pregnancy outcomes and increased maternal type 2 diabetes mellitus (T2DM) risk. The GenDiP Consortium conducted trans-generational, multi-ancestry genome-wide association study meta-analyses of GDM and pregnancy glycemic traits in up to 38,305 GDM cases and 776,145 controls. We identified 37 GDM-associated loci (19 novel) and five novel loci for glycemic traits, all operating through the maternal genome. Most GDM loci overlapped with T2DM and non-pregnant glycemic traits, with limited evidence for pregnancy-specific effects. MTNR1B showed pregnancy-enhanced effects on 2-hour glucose, potentially mediated by interaction with GPR61, a novel GDM locus, suggesting a gestation-specific melatonin-glucose signalling axis. We also observed ancestry-specific effects at the fasting glucose locus ABCB11, with opposite directions in European and East Asian populations. Our findings provide new insights into the genetic architecture of GDM and highlight the need for larger, ancestrally diverse studies.

U2 - 10.1101/2025.08.19.25333735

DO - 10.1101/2025.08.19.25333735

M3 - Preprint

BT - Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects

PB - medRxiv

ER -

Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects

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