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 36 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%

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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“…Deciphering the genetic basis of the maternal phenome, when combined with birth cohort family sequencing data, enables investigations into maternal intrauterine and fetal genetic effects on birth outcome and, subsequently, long-term children’s health 26–28 . Secondly, it is worthwhile to enhance the sequencing depth and length of specific samples, especially those of case samples, to obtain a spectrum of Indel and SVs alongside SNP genetic markers underlying adverse pregnancy and birth outcomes 29,30 . Thirdly, for many women, pregnancy screening represents their first comprehensive physical examination in life.…”

Section: Discussionmentioning

confidence: 99%

Utilizing Non-Invasive Prenatal Test Sequencing Data Resource for Human Genetic Investigation

Liu,

Huang,

Liu

et al. 2023

Preprint

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SummaryNon-invasive prenatal testing (NIPT) employs ultra-low-pass sequencing of maternal plasma cell-free DNA to detect fetal trisomy. With exceptional sensitivity, specificity, and safety, NIPT has gained global adoption, exceeding ten million tests, establishing it as one of the largest human genetic resources. This resource holds immense potential for exploring population genetic variations and their correlations with phenotypes. Here, we present comprehensive methods tailored for analyzing large, low-depth NIPT genetic datasets, involving customized algorithms and software for genetic variation detection, genotype imputation, and genome-wide association analysis. Through evaluations, we demonstrate that, when integrated with appropriate probabilistic models and population-specific haplotype reference panels, accurate allele frequency estimation and high genotype imputation accuracy (0.8 to 0.9) are achievable for genetic variants with alternative allele frequencies between 0.01 and 0.05, at sequencing depths of 0.1x to 0.25x. Additionally, we attained an R-square exceeding 0.9 for estimating genetic effect sizes across various sequencing platforms. These findings establish a robust theoretical and practical foundation for leveraging NIPT data in advancing medical genetic studies, not only in realms of maternal and child health, but also for long-term health outcomes.HighlightsIntroduction of probabilistic model integration for analyzing large-scale, low-pass non-invasive prenatal test (NIPT) sequencing dataEvaluation of protocols for variant detection, genotype imputation, and genome-wide association analyses with NIPT data

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

Cited by 36 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

Utilizing Non-Invasive Prenatal Test Sequencing Data Resource for Human Genetic Investigation

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