Integrating genomic studies of gestational duration and birth weight to understand maternal and fetal causes of adverse pregnancy outcomes and links with later diseases

整合妊娠持续时间和出生体重的基因组研究，以了解不良妊娠结局的母体和胎儿原因以及与以后疾病的联系

• 批准号: 10642686
• 负责人: Rachel Freathy
• 金额: $ 46.63万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642686
• 关键词: Adult; Biological Markers; Birth; Birth Weight; Child; Childhood; Clinical; Complex; Correlation Studies; DNA; Data; Disease; Dissection; Electronic Health Record; Equation; Etiology; European ancestry; Fetal Growth; Genetic; Genetic Diseases; Genome; Genomics; Gestational surrogate; Health; Human; Human Biology; Infant; Inflammatory; Intervention; Joints; Knowledge; Late-Onset Disorder; Life Cycle Stages; Link; Measures; Methods; Modeling; Molecular; Mothers; Outcome; Pathway Analysis; Pathway interactions; Perinatal mortality demographics; Phenotype; Population Heterogeneity; Pregnancy; Pregnancy Outcome; Premature Birth; Research; Research Personnel; Sample Size; Shapes; Statistical Methods; Testing; Therapeutic; Transcend; Variant; Work; adverse birth outcomes; adverse pregnancy outcome; biobank; fetal; genetic variant; genome wide association study; genome-wide; genomic locus; insight; large datasets; multiple omics; novel; perinatal morbidity; phenomics; phenotypic data; prevent; success

Project Summary/Abstract Gestational duration and birth weight are primary indicators of pregnancy outcomes. They are associated with perinatal morbidity and mortality and also with childhood and adult disorders. In the past several years, we have made substantial progress in the genomic research of gestational duration and birth weight. First, we conducted large-scale genome-wide association (GWA) studies and identified six maternal genomic loci associated with gestational duration, and 190 maternal or fetal loci associated with birth weight. Second, we developed statistical methods to dissect the maternal and fetal genetic effects on birth outcomes. Third, we have studied the causal relationships between maternal phenotypes and birth outcomes as well as the life course associations between birth outcomes and late onset disorders. Despite these successes, there is a major gap in previous genomic studies – they usually targeted either gestational duration or birth weight separately albeit these two birth outcomes are statistically correlated and biologically related. To bridge this gap, we – the leading investigators who previously focused on either gestational duration or birth weight separately – have committed to work together and integrate the genomic research of gestational duration or birth weight. We propose a novel statistical approach to jointly model the maternal and fetal genetic effects on gestational duration and fetal growth. Specifically, we will 1) use birth weight as a surrogate for gestational duration and leverage UK Biobank birth weight data for more powerful GWA discoveries of genomic loci associated with gestational duration; 2) disentangle and replicate maternal and fetal effects by integrated genomic analysis in mother/infant duos; and 3) integrate genomics and phenomics to resolve the complexity of birth outcomes and their links with late onset diseases. These cohesive study aims transcend conventional GWA studies and the results generated from this study will increase our knowledge of the biology of human birth timing and fetal growth. This study also has the potential to inform preventative and therapeutic measures for preterm birth and adverse pregnancy outcomes.

项目概要/摘要 妊娠持续时间和出生体重是妊娠结局的主要指标。 围产期发病率和死亡率以及儿童和成人疾病 在过去几年中，我们已经做到了这一点。 首先，我们在妊娠时长和出生体重的基因组研究方面取得了实质性进展。 大规模全基因组关联（GWA）研究并确定了与 妊娠持续时间以及 190 个与出生体重相关的母亲或胎儿位点 其次，我们进行了统计。 剖析母体和胎儿遗传对出生结果影响的方法第三，我们研究了因果关系。 母亲表型与出生结果之间的关系以及生命历程之间的关联 尽管取得了这些成功，但先前的基因组研究仍存在重大差距。 研究——他们通常分别针对妊娠持续时间或出生体重，尽管这两次出生 结果具有统计相关性和生物学相关性，为了弥补这一差距，我们——主要的研究人员。 以前分别关注妊娠持续时间或出生体重的人 – 已经致力于工作 我们提出了一种新的统计方法，将妊娠持续时间或出生体重的基因组研究整合在一起。 联合模拟母体和胎儿遗传对妊娠持续时间和胎儿生长的影响的方法。 具体来说，我们将 1) 使用出生体重作为妊娠持续时间的替代指标，并利用英国生物银行的出生数据 与妊娠持续时间相关的基因组位点的更强大的 GWA 发现的权重数据 2) 通过母婴二人组的综合基因组分析来解开并复制母体和胎儿的影响；以及 3）整合基因组学和表型组学来解决出生结果的复杂性及其与晚发的联系 这些有凝聚力的研究目标超越了传统的 GWA 研究及其产生的结果。 这项研究将增加我们对人类出生时间和胎儿生长的生物学知识。 为早产和不良妊娠结局的预防和治疗措施提供信息的潜力。

项目成果

Mosaic patterns of selection in genomic regions associated with diverse human traits.

• DOI: 10.1371/journal.pgen.1010494
• 发表时间: 2022-11
• 期刊: PLoS genetics
• 影响因子: 4.5

Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes.

• DOI: 10.1186/s12916-023-03167-0
• 发表时间: 2024-01-29
• 期刊: BMC MEDICINE
• 影响因子: 9.3
• 作者: Borges, Maria Carolina;Clayton, Gemma L.;Freathy, Rachel M.;Felix, Janine F.;Fernandez-Sanles, Alba;Soares, Ana Goncalves;Kilpi, Fanny;Yang, Qian;Mceachan, Rosemary R. C.;Richmond, Rebecca C.;Liu, Xueping;Skotte, Line;Irizar, Amaia;Hattersley, Andrew T.;Bodinier, Barbara;Scholtens, Denise M.;Nohr, Ellen A.;Bond, Tom A.;Hayes, M. Geoffrey;West, Jane;Tyrrell, Jessica;Wright, John;Bouchard, Luigi;Murcia, Mario;Bustamante, Mariona;Chadeau-Hyam, Marc;Jarvelin, Marjo-Riitta;Vrijheid, Martine;Perron, Patrice;Magnus, Per;Gaillard, Romy;Jaddoe, Vincent W. V.;Lowe, William L.;Feenstra, Bjarke;Hivert, Marie-France;Sorensen, Thorkild I. A.;Haberg, Siri E.;Serbert, Sylvain;Magnus, Maria;Lawlor, Deborah A.
• 通讯作者: Lawlor, Deborah A.

Author Correction: Genetic effects on the timing of parturition and links to fetal birth weight.

• DOI: 10.1038/s41588-023-01412-z
• 发表时间: 2023-07
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Sole-Navais, Pol;Flatley, Christopher;Steinthorsdottir, Valgerdur;Vaudel, Marc;Juodakis, Julius;Chen, Jing;Laisk, Triin;LaBella, Abigail L.;Westergaard, David;Bacelis, Jonas;Brumpton, Ben;Skotte, Line;Borges, Maria C.;Helgeland, Oyvind;Mahajan, Anubha;Wielscher, Matthias;Lin, Frederick;Briggs, Catherine;Wang, Carol A.;Moen, Gunn-Helen;Beaumont, Robin N.;Bradfield, Jonathan P.;Abraham, Abin;Thorleifsson, Gudmar;Gabrielsen, Maiken E.;Ostrowski, Sisse R.;Modzelewska, Dominika;Nohr, Ellen A.;Hypponen, Elina;Srivastava, Amit;Talbot, Octavious;Allard, Catherine;Williams, Scott M.;Menon, Ramkumar;Shields, Beverley M.;Sveinbjornsson, Gardar;Xu, Huan;Melbye, Mads;Lowe, William, Jr.;Bouchard, Luigi;Oken, Emily;Pedersen, Ole B.;Gudbjartsson, Daniel F.;Erikstrup, Christian;Sorensen, Erik;Lie, Rolv T.;Teramo, Kari;Hallman, Mikko;Juliusdottir, Thorhildur;Hakonarson, Hakon;Ullum, Henrik;Hattersley, Andrew T.;Sletner, Line;Merialdi, Mario;Rifas-Shiman, Sheryl L.;Steingrimsdottir, Thora;Scholtens, Denise;Power, Christine;West, Jane;Nyegaard, Mette;Capra, John A.;Skogholt, Anne H.;Magnus, Per;Andreassen, Ole A.;Thorsteinsdottir, Unnur;Grant, Struan F. A.;Qvigstad, Elisabeth;Pennell, Craig E.;Hivert, Marie-France;Hayes, Geoffrey M.;Jarvelin, Marjo-Riitta;McCarthy, Mark I.;Lawlor, Deborah A.;Nielsen, Henriette S.;Magi, Reedik;Rokas, Antonis;Hveem, Kristian;Stefansson, Kari;Feenstra, Bjarke;Njolstad, Pal;Muglia, Louis J.;Freathy, Rachel M.;Johansson, Stefan;Zhang, Ge;Jacobsson, Bo
• 通讯作者: Jacobsson, Bo

GSEL: a fast, flexible python package for detecting signatures of diverse evolutionary forces on genomic regions.

• DOI: 10.1093/bioinformatics/btad037
• 发表时间: 2023-01-01
• 期刊: Bioinformatics (Oxford, England)

Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study.

• DOI: 10.1016/j.ebiom.2023.104441
• 发表时间: 2023-02
• 期刊: EBIOMEDICINE
• 影响因子: 11.1
• 作者: Zhao, Jian;Stewart, Isobel D.;Baird, Denis;Mason, Dan;Wright, John;Zheng, Jie;Gaunt, Tom R.;Evans, David M.;Freathy, Rachel M.;Langenberg, Claudia;Warrington, Nicole M.;Lawlor, Deborah A.;Borges, Maria Carolina
• 通讯作者: Borges, Maria Carolina