Genetic effects on the timing of parturition and links to fetal birth weight

Pol Solé-Navais; Christopher Flatley; Valgerdur Steinthorsdottir; Marc Vaudel; Julius Juodakis; Jing Chen; Triin Laisk; Abigail L LaBella; David Westergaard; Jonas Bacelis; Ben Brumpton; Line Skotte; Maria C Borges; Øyvind Helgeland; Anubha Mahajan; Matthias Wielscher; Frederick Lin; Catherine Briggs; Carol A Wang; Gunn-Helen Moen; Robin N Beaumont; Jonathan P Bradfield; Abin Abraham; Gudmar Thorleifsson; Maiken E Gabrielsen; Sisse R Ostrowski; Dominika Modzelewska; Ellen A Nohr; Elina Hypponen; Amit Srivastava; Octavious Talbot; Catherine Allard; Scott M Williams; Ramkumar Menon; Beverley M Shields; Gardar Sveinbjornsson; Huan Xu; Mads Melbye; William Lowe; Luigi Bouchard; Emily Oken; Ole B Pedersen; Daniel F Gudbjartsson; Christian Erikstrup; Erik Sørensen; Early Growth Genetics Consortium; Rolv T Lie; Kari Teramo; Mikko Hallman; Thorhildur Juliusdottir; Hakon Hakonarson; Henrik Ullum; Andrew T Hattersley; Line Sletner; Mario Merialdi; Sheryl L Rifas-Shiman; Thora Steingrimsdottir; Denise Scholtens; Christine Power; Jane West; Mette Nyegaard; John A Capra; Anne H Skogholt; Per Magnus; Ole A Andreassen; Unnur Thorsteinsdottir; Struan F A Grant; Elisabeth Qvigstad; Craig E Pennell; Marie-France Hivert; Geoffrey M Hayes; Marjo-Riitta Jarvelin; Mark I McCarthy; Deborah A Lawlor; Henriette S Nielsen; Reedik Mägi; Antonis Rokas; Kristian Hveem; Kari Stefansson; Bjarke Feenstra; Pål Njolstad; Louis J Muglia; Rachel M Freathy; Stefan Johanson; Ge Zhang; Bo Jacobsson; Estonian Biobank Research Team; Danish Blood Donor Study Genomic Cohort

doi:10.1038/s41588-023-01343-9

Genetic effects on the timing of parturition and links to fetal birth weight

Pol Solé-Navais, Christopher Flatley, Valgerdur Steinthorsdottir, Marc Vaudel, Julius Juodakis, Jing Chen, Triin Laisk, Abigail L LaBella, David Westergaard, Jonas Bacelis, Ben Brumpton, Line Skotte, Maria C Borges, Øyvind Helgeland, Anubha Mahajan, Matthias Wielscher, Frederick Lin, Catherine Briggs, Carol A Wang, Gunn-Helen MoenRobin N Beaumont, Jonathan P Bradfield, Abin Abraham, Gudmar Thorleifsson, Maiken E Gabrielsen, Sisse R Ostrowski, Dominika Modzelewska, Ellen A Nohr, Elina Hypponen, Amit Srivastava, Octavious Talbot, Catherine Allard, Scott M Williams, Ramkumar Menon, Beverley M Shields, Gardar Sveinbjornsson, Huan Xu, Mads Melbye, William Lowe, Luigi Bouchard, Emily Oken, Ole B Pedersen, Daniel F Gudbjartsson, Christian Erikstrup, Erik Sørensen, Early Growth Genetics Consortium, Rolv T Lie, Kari Teramo, Mikko Hallman, Thorhildur Juliusdottir, Hakon Hakonarson, Henrik Ullum, Andrew T Hattersley, Line Sletner, Mario Merialdi, Sheryl L Rifas-Shiman, Thora Steingrimsdottir, Denise Scholtens, Christine Power, Jane West, Mette Nyegaard, John A Capra, Anne H Skogholt, Per Magnus, Ole A Andreassen, Unnur Thorsteinsdottir, Struan F A Grant, Elisabeth Qvigstad, Craig E Pennell, Marie-France Hivert, Geoffrey M Hayes, Marjo-Riitta Jarvelin, Mark I McCarthy, Deborah A Lawlor, Henriette S Nielsen, Reedik Mägi, Antonis Rokas, Kristian Hveem, Kari Stefansson, Bjarke Feenstra, Pål Njolstad, Louis J Muglia, Rachel M Freathy, Stefan Johanson, Ge Zhang, Bo Jacobsson, Estonian Biobank Research Team, Danish Blood Donor Study Genomic Cohort

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Abstract

The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.

Original language	English
Journal	Nature Genetics
Volume	55
Issue number	4
Pages (from-to)	559-567
Number of pages	9
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-023-01343-9
Publication status	Published - Apr 2023

Bibliographical note

Correction to this article has been published: https://doi.org/10.1038/s41588-023-01412-z
In the version of this article originally published, the surname of author Stefan Johansson was misspelled as Johanson. In the abstract and “Genome-wide association analyses” section of the Results, the number of loci associated with preterm birth was shown as six instead of seven. In addition, there was a production error in the Figure 1a y-axis units shown below 0, where “10” and “20” were shown as negative numbers. The errors have been corrected in the HTML and PDF versions of the article.
© 2023. The Author(s).

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Solé-Navais, P., Flatley, C., Steinthorsdottir, V., Vaudel, M., Juodakis, J., Chen, J., Laisk, T., LaBella, A. L., Westergaard, D., Bacelis, J., Brumpton, B., Skotte, L., Borges, M. C., Helgeland, Ø., Mahajan, A., Wielscher, M., Lin, F., Briggs, C., Wang, C. A., ... Danish Blood Donor Study Genomic Cohort (2023). Genetic effects on the timing of parturition and links to fetal birth weight. Nature Genetics, 55(4), 559-567. Advance online publication. https://doi.org/10.1038/s41588-023-01343-9

@article{b6024a2bd8754087bf59330ae5789016,

title = "Genetic effects on the timing of parturition and links to fetal birth weight",

abstract = "The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.",

author = "Pol Sol{\'e}-Navais and Christopher Flatley and Valgerdur Steinthorsdottir and Marc Vaudel and Julius Juodakis and Jing Chen and Triin Laisk and LaBella, {Abigail L} and David Westergaard and Jonas Bacelis and Ben Brumpton and Line Skotte and Borges, {Maria C} and {\O}yvind Helgeland and Anubha Mahajan and Matthias Wielscher and Frederick Lin and Catherine Briggs and Wang, {Carol A} and Gunn-Helen Moen and Beaumont, {Robin N} and Bradfield, {Jonathan P} and Abin Abraham and Gudmar Thorleifsson and Gabrielsen, {Maiken E} and Ostrowski, {Sisse R} and Dominika Modzelewska and Nohr, {Ellen A} and Elina Hypponen and Amit Srivastava and Octavious Talbot and Catherine Allard and Williams, {Scott M} and Ramkumar Menon and Shields, {Beverley M} and Gardar Sveinbjornsson and Huan Xu and Mads Melbye and William Lowe and Luigi Bouchard and Emily Oken and Pedersen, {Ole B} and Gudbjartsson, {Daniel F} and Christian Erikstrup and Erik S{\o}rensen and {Early Growth Genetics Consortium} and Lie, {Rolv T} and Kari Teramo and Mikko Hallman and Thorhildur Juliusdottir and Hakon Hakonarson and Henrik Ullum and Hattersley, {Andrew T} and Line Sletner and Mario Merialdi and Rifas-Shiman, {Sheryl L} and Thora Steingrimsdottir and Denise Scholtens and Christine Power and Jane West and Mette Nyegaard and Capra, {John A} and Skogholt, {Anne H} and Per Magnus and Andreassen, {Ole A} and Unnur Thorsteinsdottir and Grant, {Struan F A} and Elisabeth Qvigstad and Pennell, {Craig E} and Marie-France Hivert and Hayes, {Geoffrey M} and Marjo-Riitta Jarvelin and McCarthy, {Mark I} and Lawlor, {Deborah A} and Nielsen, {Henriette S} and Reedik M{\"a}gi and Antonis Rokas and Kristian Hveem and Kari Stefansson and Bjarke Feenstra and P{\aa}l Njolstad and Muglia, {Louis J} and Freathy, {Rachel M} and Stefan Johanson and Ge Zhang and Bo Jacobsson and {Estonian Biobank Research Team} and {Danish Blood Donor Study Genomic Cohort}",

note = "Correction to this article has been published: https://doi.org/10.1038/s41588-023-01412-z In the version of this article originally published, the surname of author Stefan Johansson was misspelled as Johanson. In the abstract and “Genome-wide association analyses” section of the Results, the number of loci associated with preterm birth was shown as six instead of seven. In addition, there was a production error in the Figure 1a y-axis units shown below 0, where “10” and “20” were shown as negative numbers. The errors have been corrected in the HTML and PDF versions of the article. {\textcopyright} 2023. The Author(s).",

year = "2023",

month = apr,

doi = "10.1038/s41588-023-01343-9",

language = "English",

volume = "55",

pages = "559--567",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

}

Solé-Navais, P, Flatley, C, Steinthorsdottir, V, Vaudel, M, Juodakis, J, Chen, J, Laisk, T, LaBella, AL, Westergaard, D, Bacelis, J, Brumpton, B, Skotte, L, Borges, MC, Helgeland, Ø, Mahajan, A, Wielscher, M, Lin, F, Briggs, C, Wang, CA, Moen, G-H, Beaumont, RN, Bradfield, JP, Abraham, A, Thorleifsson, G, Gabrielsen, ME, Ostrowski, SR, Modzelewska, D, Nohr, EA, Hypponen, E, Srivastava, A, Talbot, O, Allard, C, Williams, SM, Menon, R, Shields, BM, Sveinbjornsson, G, Xu, H, Melbye, M, Lowe, W, Bouchard, L, Oken, E, Pedersen, OB, Gudbjartsson, DF, Erikstrup, C, Sørensen, E, Early Growth Genetics Consortium, Lie, RT, Teramo, K, Hallman, M, Juliusdottir, T, Hakonarson, H, Ullum, H, Hattersley, AT, Sletner, L, Merialdi, M, Rifas-Shiman, SL, Steingrimsdottir, T, Scholtens, D, Power, C, West, J, Nyegaard, M, Capra, JA, Skogholt, AH, Magnus, P, Andreassen, OA, Thorsteinsdottir, U, Grant, SFA, Qvigstad, E, Pennell, CE, Hivert, M-F, Hayes, GM, Jarvelin, M-R, McCarthy, MI, Lawlor, DA, Nielsen, HS, Mägi, R, Rokas, A, Hveem, K, Stefansson, K, Feenstra, B, Njolstad, P, Muglia, LJ, Freathy, RM, Johanson, S, Zhang, G, Jacobsson, B, Estonian Biobank Research Team & Danish Blood Donor Study Genomic Cohort 2023, 'Genetic effects on the timing of parturition and links to fetal birth weight', Nature Genetics, vol. 55, no. 4, pp. 559-567. https://doi.org/10.1038/s41588-023-01343-9

TY - JOUR

T1 - Genetic effects on the timing of parturition and links to fetal birth weight

AU - Solé-Navais, Pol

AU - Flatley, Christopher

AU - Steinthorsdottir, Valgerdur

AU - Vaudel, Marc

AU - Juodakis, Julius

AU - Chen, Jing

AU - Laisk, Triin

AU - LaBella, Abigail L

AU - Westergaard, David

AU - Bacelis, Jonas

AU - Brumpton, Ben

AU - Skotte, Line

AU - Borges, Maria C

AU - Helgeland, Øyvind

AU - Mahajan, Anubha

AU - Wielscher, Matthias

AU - Lin, Frederick

AU - Briggs, Catherine

AU - Wang, Carol A

AU - Moen, Gunn-Helen

AU - Beaumont, Robin N

AU - Bradfield, Jonathan P

AU - Abraham, Abin

AU - Thorleifsson, Gudmar

AU - Gabrielsen, Maiken E

AU - Ostrowski, Sisse R

AU - Modzelewska, Dominika

AU - Nohr, Ellen A

AU - Hypponen, Elina

AU - Srivastava, Amit

AU - Talbot, Octavious

AU - Allard, Catherine

AU - Williams, Scott M

AU - Menon, Ramkumar

AU - Shields, Beverley M

AU - Sveinbjornsson, Gardar

AU - Xu, Huan

AU - Melbye, Mads

AU - Lowe, William

AU - Bouchard, Luigi

AU - Oken, Emily

AU - Pedersen, Ole B

AU - Gudbjartsson, Daniel F

AU - Erikstrup, Christian

AU - Sørensen, Erik

AU - Early Growth Genetics Consortium

AU - Lie, Rolv T

AU - Teramo, Kari

AU - Hallman, Mikko

AU - Juliusdottir, Thorhildur

AU - Hakonarson, Hakon

AU - Ullum, Henrik

AU - Hattersley, Andrew T

AU - Sletner, Line

AU - Merialdi, Mario

AU - Rifas-Shiman, Sheryl L

AU - Steingrimsdottir, Thora

AU - Scholtens, Denise

AU - Power, Christine

AU - West, Jane

AU - Nyegaard, Mette

AU - Capra, John A

AU - Skogholt, Anne H

AU - Magnus, Per

AU - Andreassen, Ole A

AU - Thorsteinsdottir, Unnur

AU - Grant, Struan F A

AU - Qvigstad, Elisabeth

AU - Pennell, Craig E

AU - Hivert, Marie-France

AU - Hayes, Geoffrey M

AU - Jarvelin, Marjo-Riitta

AU - McCarthy, Mark I

AU - Lawlor, Deborah A

AU - Nielsen, Henriette S

AU - Mägi, Reedik

AU - Rokas, Antonis

AU - Hveem, Kristian

AU - Stefansson, Kari

AU - Feenstra, Bjarke

AU - Njolstad, Pål

AU - Muglia, Louis J

AU - Freathy, Rachel M

AU - Johanson, Stefan

AU - Zhang, Ge

AU - Jacobsson, Bo

AU - Estonian Biobank Research Team

AU - Danish Blood Donor Study Genomic Cohort

N1 - Correction to this article has been published: https://doi.org/10.1038/s41588-023-01412-z In the version of this article originally published, the surname of author Stefan Johansson was misspelled as Johanson. In the abstract and “Genome-wide association analyses” section of the Results, the number of loci associated with preterm birth was shown as six instead of seven. In addition, there was a production error in the Figure 1a y-axis units shown below 0, where “10” and “20” were shown as negative numbers. The errors have been corrected in the HTML and PDF versions of the article. © 2023. The Author(s).

PY - 2023/4

Y1 - 2023/4

N2 - The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.

AB - The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.

UR - http://www.scopus.com/inward/record.url?scp=85151699870&partnerID=8YFLogxK

U2 - 10.1038/s41588-023-01343-9

DO - 10.1038/s41588-023-01343-9

M3 - Journal article

C2 - 37012456

SN - 1061-4036

VL - 55

SP - 559

EP - 567

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

Genetic effects on the timing of parturition and links to fetal birth weight

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