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; Rolv T Lie; Kari Teramo; Mikko Hallman; Thorhildur Juliusdottir; Henrik Ullum; Early Growth Genetics Consortium; Henriette  Svarre Nielsen

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, Rolv T Lie, Kari Teramo, Mikko Hallman, Thorhildur Juliusdottir, Henrik Ullum, Early Growth Genetics Consortium, Henriette Svarre Nielsen

^*Corresponding author for this work

58 Citations (Scopus)

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

Keywords

Birth Weight/genetics
Female
Gestational Age
Humans
Infant, Newborn
Parturition/genetics
Pregnancy
Premature Birth/genetics

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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., ... Svarre Nielsen, H. (2023). Genetic effects on the timing of parturition and links to fetal birth weight. Nature Genetics, 55(4), 559-567. https://doi.org/10.1038/s41588-023-01343-9

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, Lie, RT, Teramo, K, Hallman, M, Juliusdottir, T, Ullum, H, Early Growth Genetics Consortium & Svarre Nielsen, H 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

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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.",

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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 - Lie, Rolv T

AU - Teramo, Kari

AU - Hallman, Mikko

AU - Juliusdottir, Thorhildur

AU - Ullum, Henrik

AU - Early Growth Genetics Consortium

AU - Svarre Nielsen, Henriette

PY - 2023/4

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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.

KW - Birth Weight/genetics

KW - Female

KW - Gestational Age

KW - Humans

KW - Infant, Newborn

KW - Parturition/genetics

KW - Pregnancy

KW - Premature Birth/genetics

UR - https://www.scopus.com/pages/publications/85151699870

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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Keywords

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