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

Solé-Navais, Pol; Flatley, Christopher; Steinthórsdóttir, Valgerður; Vaudel, Marc; Juodakis, Julius; Chen, Jing; Laisk, Triin; LaBella, Abigail L.; Westergaard, David; Bacelis, Jonas; Brumpton, Ben; Skotte, Line; Borges, Maria Carolina; Helgeland, Øyvind; Wielscher, Matthias; Lin, Frederick; Briggs, Catherine; Wang, Carol A.; Moen, Gunn-Helen; Beaumont, Robin N; Bradfield, Jonathan P.; Abraham, Abin; Þorleifsson, Guðmar; Gabrielsen, Maiken Elvestad; Ostrowski, Sisse Rye; Modzelewska, Dominika; Nøhr, Ellen A.; Hyppönen, Elina; Srivastava, Amit; Talbot, Octavious; Allard, Catherine; Williams, Scott M.; Menon, Ramkumar; Shields, Beverley M.; Sveinbjörnsson, Garðar; Xu, Huan; Melbye, Mads; Lowe, William L.; Bouchard, Luigi; Oken, Emily; Pedersen, Ole Birger; Guðbjartsson, Daníel F.; Erikstrup, Christian; Sørensen, Erik; Lie, Rolv Terje; Teramo, Kari; Hallman, Mikko; Juliusdottir, Thorhildur; Hákonarson, Hákon; Ullum, Henrik; Hattersley, Andrew T.; Sletner, Line; Merialdi, Mario; Rifas‐Shiman, Sheryl L.; Steingrímsdóttir, Þóra; Scholtens, Denise M.; Power, Christine; West, Jane; Nyegaard, Mette; Capra, John A.; Skogholt, Anne Heidi; Magnus, Per; Andreassen, Ole A.; Þorsteinsdóttir, Unnur; Grant, Struan F A; Qvigstad, Elisabeth; Pennell, Craig E.; Hivert, Marie‐France; Hayes, M. Geoffrey; Järvelin, Marjo‐Riitta; McCarthy, Mark; Lawlor, Debbie A.; Nielsen, Henriette Svarre; Mägi, Reedik; Rokas, Antonis; Hveem, Kristian; Stefánsson, Kāri; Feenstra, Bjarke; Njølstad, Pål R.; Muglia, Louis J.; Freathy, Rachel M.; Johansson, Stefan; Zhang, Ge; Jacobsson, Bo

doi:10.1038/s41588-023-01343-9

Cited by 22 publications

(34 citation statements)

References 67 publications

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“…For example, variation in gestation length is strongly associated with variation in body size in Primates. This finding is consistent with human genome-wide association studies (GWAS) of gestation length where some of the genetic variants that influence gestation length are also known to influence birth weight 24,25 .…”

Section: Discussionsupporting

confidence: 87%

The evolution of gestation length in eutherian mammals

Danis,

Rokas

2023

Preprint

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Gestation length, or the duration of pregnancy, is a critical component of mammalian reproductive biology. Eutherian mammals exhibit striking variation in their gestation lengths, which has traditionally been linked to and allometrically scales with variation in other life history traits, including body mass and lifespan. How the phenotypic landscape of gestation length variation, including its associations with body mass and lifespan variation, changed over mammalian evolution remains unknown. Phylogeny-informed analyses of 845 representative extant eutherian mammals showed that gestation length variation substantially differed in both whether and how strongly it was associated with body mass and lifespan across mammalian clades. For example, gestation length variation in Chiroptera and Cetacea was not associated with lifespan or body mass but was strongly associated only with body mass in Carnivora. We also identified 52 adaptive shifts in gestation length variation across the mammal phylogeny and 14 adaptive shifts when considering all three life history traits; the placements of six adaptive shifts are common in the two analyses. Notably, two of these shifts occurred at the roots of Cetacea and Pinnipedia, respectively, coinciding with the transition of these clades to the marine environment. The varying dynamics of the phenotypic landscape of gestation length, coupled with the varying patterns of associations between gestation length and two other major life history traits, raise the hypothesis that evolutionary constraints on gestation length have varied substantially across mammalian phylogeny. This variation in constraints implies that the genetic architecture of gestation length differs between mammal clades.

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Section: Discussionsupporting

confidence: 87%

The evolution of gestation length in eutherian mammals

Danis,

Rokas

2023

Preprint

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“…Further, instead of reflecting solely intrauterine growth restriction, the PGSs may be partly related to normal variation in child’s size, for example, due to gestational duration, though our results adjusting for the PGS for gestational length suggest that controlling for this has negligible effect on the disease associations (Supplementary Table 5) 17,27 . In addition, though we used established MR principles, and therefore could test for evidence of a causality of maternal effects on birth weight on disease risk, we have not performed formal MR to provide accurate effect estimates for the effects of birth weight.…”

Section: Discussionmentioning

confidence: 85%

“…As sensitivity analyses, we performed similar analyses using only one child per mother (N=28,582), in mother-child pairs where 3 th degree relatives and closer for both mothers and children had been removed from the analysis, keeping only the oldest mother and her oldest child from an extended family (N=22,454) based on relationships identified in the KING analysis 28 , and adjusting for polygenic scores for maternal effects on gestational length 17 . We also utilized the identified father-child pairs (N=31,775) to test for the presence of potential postnatal effects and to further control for potential familial effects.…”

Section: Discussionmentioning

confidence: 99%

“…Variation in birth weight has a large genetic component (SNP-based heritability (h 2 SNP being ~40%, of which a fifth can be specifically allocated to maternal genetic variation), making it an amenable trait for genetic studies 15 . However, since many different factors including both the maternal and fetal genome influence the size of the baby, using MR in assessing the DOHaD hypothesis has some important prerequisites 3,[15][16][17][18] . First, using genetic factors specifically reflecting maternal influences on birth weight as instrumental variables in MR is crucial 12,19 , as these can plausibly reflect intrauterine growth restriction as opposed to the variants with strict fetal effects.…”

Section: Introductionmentioning

confidence: 99%

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Disentangling the link between maternal influences on birth weight and disease risk in 36,211 genotyped mother-child pairs

Leinonen,

Pirinen,

Tukiainen

2023

Preprint

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Epidemiological studies have robustly linked lower birth weight to later-life disease risks. These observations may reflect the adverse impact of intrauterine growth restriction on a child's health. However, causal evidence supporting such a mechanism in humans is largely lacking. Using Mendelian Randomization and 36,211 genotyped mother-child pairs from the FinnGen study, we assessed the relationship between intrauterine growth restriction and five common health outcomes (coronary heart disease (CHD), hypertension, statin use, type 2 diabetes and cancer). We proxied intrauterine growth restriction with polygenic scores for maternal effects on birth weight and took into account transmission of genetic variants between a mother and a child in the analyses. We find limited evidence for contribution of normal variation in maternally influenced intrauterine growth on later-life disease. Instead, we find support for genetic pleiotropy in the child genome linking birth weight to CHD and hypertension. Our study illustrates the opportunities that data from genotyped parent-child pairs from a population-based biobank provides for addressing causality of maternal influences.

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“…Genetic associations for 3 of the outcomes—ectopic pregnancy, hyperemesis gravidarum, and gestational diabetes—were extracted from a database of publicly available GWAS summary statistics from FinnGen (Table). For preeclampsia, we used data from a study by Steinthorsdottir et al; for preterm birth, a study by Solé-Navais et al; and for offspring birth weight, a study by Juliusdottir et al All pregnancy outcomes were binary, except for birth weight, which was analyzed as a continuous outcome.…”

Section: Methodsmentioning

confidence: 99%

Mediating Factors in the Association of Maternal Educational Level With Pregnancy Outcomes

Rogne,

Gill,

Liew

et al. 2024

JAMA Netw Open

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ImportanceLower educational attainment is associated with increased risk of adverse pregnancy outcomes, but it is unclear which pathways mediate this association.ObjectiveTo investigate the association between educational attainment and pregnancy outcomes and the proportion of this association that is mediated through modifiable cardiometabolic risk factors.Design, Setting, and ParticipantsIn this 2-sample mendelian randomization (MR) cohort study, uncorrelated (R2 &lt; 0.01) single-nucleotide variants (formerly single-nucleotide polymorphisms) associated with the exposure (P &lt; 5 × 10−8) and mediators and genetic associations with the pregnancy outcomes from genome-wide association studies were extracted. All participants were of European ancestry and were largely from Finland, Iceland, the United Kingdom, or the US. The inverse variance–weighted method was used in the main analysis, and the weighted median, weighted mode, and MR Egger regression were used in sensitivity analyses. In mediation analyses, the direct effect of educational attainment estimated in multivariable MR was compared with the total effect estimated in the main univariable MR analysis. Data were extracted between December 1, 2022, and April 30, 2023.ExposureGenetically estimated educational attainment. The mediators considered were genetically estimated type 2 diabetes, body mass index, smoking, high-density lipoprotein cholesterol level, and systolic blood pressure.Main Outcomes and MeasuresEctopic pregnancy, hyperemesis gravidarum, gestational diabetes, preeclampsia, preterm birth, and offspring birth weight.ResultsThe analyses included 3 037 499 individuals with data on educational attainment, and those included in studies on pregnancy outcomes ranged from 141 014 for ectopic pregnancy to 270 002 with data on offspring birth weight. Each SD increase in genetically estimated educational attainment (ie, 3.4 years) was associated with an increased birth weight of 42 (95% CI, 28-56) g and an odds ratio ranging from 0.53 (95% CI, 0.46-0.60) for ectopic pregnancy to 0.81 (95% CI, 0.71-0.93) for preeclampsia. The combined proportion of the association that was mediated by the 5 cardiometabolic risk factors ranged from −17% (95% CI, −46% to 26%) for hyperemesis gravidarum to 78% (95% CI, 10%-208%) for preeclampsia. Sensitivity analyses accounting for pleiotropy were consistent with the main analyses.Conclusions and RelevanceIn this MR cohort study, intervening for type 2 diabetes, body mass index, smoking, high-density lipoprotein cholesterol level, and systolic blood pressure may lead to reductions in several adverse pregnancy outcomes associated with lower levels of education. Such public health interventions would serve to reduce health disparities attributable to social inequalities.

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

Cited by 22 publications

References 67 publications

The evolution of gestation length in eutherian mammals

The evolution of gestation length in eutherian mammals

Disentangling the link between maternal influences on birth weight and disease risk in 36,211 genotyped mother-child pairs

Mediating Factors in the Association of Maternal Educational Level With Pregnancy Outcomes

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