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

项目总结/摘要 妊娠期和出生体重是妊娠结局的主要指标。与其关联 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 在妊娠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 大规模的全基因组关联（GWA）研究，并确定了六个与 妊娠持续时间和190个与出生体重相关的母体或胎儿基因座。第二，我们统计了 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。 母体表型和出生结果之间的关系以及 出生结果和迟发性疾病。尽管取得了这些成功，但在以前的基因组研究中存在重大差距。 研究-他们通常分别针对妊娠期或出生体重，尽管这两个出生 结果在统计学上是相关的，在生物学上是相关的。为了弥合这一差距，我们-主要的调查人员 以前分别关注妊娠期或出生体重的人， 并整合妊娠期或出生体重的基因组研究。我们提出了一个新的统计 方法共同模拟母体和胎儿遗传对妊娠期和胎儿生长的影响。 具体来说，我们将1）使用出生体重作为妊娠期的替代品，并利用英国生物银行的出生 与妊娠持续时间相关的基因组位点的更强大的GWA发现的重量数据; 2） 通过母亲/婴儿二人组的综合基因组分析，解开并复制母亲和胎儿的影响;以及 3)整合基因组学和表型组学，以解决出生结果的复杂性及其与晚发型的联系 疾病这些凝聚力的研究目标超越了传统的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的生物学知识。这项研究也有 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.