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

项目摘要/摘要 妊娠持续时间和出生体重是妊娠结局的主要指标。它们与以下内容相关 围产期发病率和死亡率以及儿童和成人疾病。在过去的几年里，我们已经 在孕期和出生体重的基因组研究方面取得了实质性进展。首先，我们进行了 大规模全基因组关联(GWA)研究并确定了六个与以下因素相关的母体基因组基因座 孕期和190个与出生体重相关的母体或胎儿基因座。第二，我们发展了统计学 方法剖析母婴遗传对出生结局的影响。第三，我们研究了因果关系 母体表型与出生结局的关系以及母体表型与产程的关系 出生结局和迟发性精神障碍。尽管取得了这些成功，但在以前的基因组中仍有一个重大差距 研究-他们通常分别针对妊娠持续时间或出生体重，尽管这两个出生 结果在统计上是相关的，在生物学上也是相关的。为了弥合这一鸿沟，我们--主要调查人员 以前分别关注妊娠持续时间或出生体重的人-已经承诺工作 共同整合孕期或出生体重的基因组研究。我们提出了一种新的统计方法 母婴遗传对妊娠持续时间和胎儿生长影响的联合建模方法。 具体地说，我们将1)使用出生体重作为孕期的替代指标，并利用英国生物库出生 更强大的GWA发现与妊娠持续时间相关的基因组基因座的权重数据；2) 通过母婴二人组的综合基因组分析，分离和复制母婴效应；以及 3)整合基因组学和表型组学，以解决生育结局的复杂性及其与晚发的联系 疾病。这些衔接研究的目标超越了传统的GWA研究和由此产生的结果 这项研究将增加我们对人类出生时间和胎儿生长生物学的了解。这项研究还包括 有可能为早产和不良妊娠结局的预防和治疗措施提供信息。

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.