Integrative omics of preeclampsia in TOPMED and maternal cardiovascular health

先兆子痫（PE）是妊娠20周后新发高血压和蛋白尿的发展，是一种高血压疾病， 由胎盘介导的严重妊娠特异性疾病，影响所有妊娠的5%。妇女 既往PE导致心血管疾病（包括缺血性心脏病）的终生风险增加2 - 4倍， 中风PE的潜在病因仍然知之甚少;因此， 选择仍然有限。PE具有估计为55 - 60%的实质性遗传成分， 胎儿的贡献，估计分别为30 - 35%和20%。在理解PE遗传学方面的进展 落后于其他疾病由于：两个基因组（母亲和胎儿）的参与，疾病异质性， 从许多大型队列研究中排除产科表型，以及缺乏足够的 样本大小的权力，以确定遗传风险基因座。除了遗传学，使用其他组学策略对PE进行分析 已经确定了转录组学、蛋白质组学和代谢组学的改变，这些改变先于疾病。然而，PE队列 在相同的表型良好的个体上进行多组学分析是缺乏的。应对这些挑战和 进一步了解PE病理生理学，我们建议利用TOPM数据在"波士顿-哥伦比亚" 合作不良妊娠结局研究"，利用两个大型，多种族妊娠 队列，LIFECODES（波士顿）和GenPE（哥伦比亚）。LIFECODES是一种持续的纵向妊娠 队列（2009年至今，N> 3000例妊娠，152例PE病例），其中母体样本来自 妊娠和分娩样本。GenPE是一项哥伦比亚研究（2000 - 2012，N = 3260例病例，4331例对照） 用于识别母体和胎儿的遗传风险变异。具体来说，对于这一提议，我们将利用 TOPMed X01还资助了整个LIFECODES和GenPE队列的全基因组测序（WGS）， 作为深入的多组学分析（代谢，循环微粒蛋白质组学和转录组学） LIFECODES中匹配的PE病例对照样本中的产前血浆样本，预计可用 在开始日期之前。我们提出三个具体目标。首先，我们将进行基因发现 使用常见变异、罕见变异、基于基因和母胎相互作用分析来评估先兆子痫。第二、 我们将在匹配的PE病例中对所有产前血浆样本进行纵向深入的多组学分析， 对照样本以识别PE的分子亚型，并将其与已知和新型遗传变异联系起来。第三、 我们将测试PE的多基因风险评分，辅以纵向分子和临床表型， 预测产妇分娩时发病率和未来心血管疾病。综合分析，这一多... TOPMed中PE的组学项目，以及在独立队列中的复制，将产生新的见解， 先兆子痫的病因由于不良的妊娠结局大大增加了未来的风险， 受影响妇女的心脏代谢疾病，提高对妊娠相关 这些疾病将加强改善妇女健康和预防未来心血管疾病的战略。

Preeclampsia (PE), the development of new-onset hypertension and proteinuria after 20 weeks gestation, is a severe pregnancy-specific disorder mediated by the placenta that affects 5% of all pregnancies. Women with prior PE have an 2-4 fold increased lifetime risk of cardiovascular disease, including ischemic heart disease and stroke. The underlying etiology of PE remains poorly understood; consequently, predictive and therapeutic options remain limited. PE has a substantial heritable component estimated at 55-60%, with both maternal and fetal contributions, estimated at 30-35% and 20%, respectively. Progress in understanding PE genetics has lagged other disorders due to: the involvement of two genomes (maternal and fetal), disease heterogeneity, the exclusion of obstetric phenotypes from many large cohort studies, and the lack of PE collections of adequate sample size for power to identify genetic risk loci. Beyond genetics, profiling of PE using other omic strategies has identified transcriptomic, proteomic, and metabolomic alterations that precede disease. However, PE cohorts with multiple omics on the same well-phenotyped individuals are lacking. To address these challenges and advance understanding of PE pathophysiology, we propose to leverage TOPMed data in the “Boston-Colombia Collaborative Adverse Pregnancy Outcome study” which capitalizes on two large, multi-ethnic pregnancy cohorts, LIFECODES (Boston) and GenPE (Colombia). LIFECODES is an ongoing longitudinal pregnancy cohort (2009–present, N >3000 pregnancies, 152 PE cases) with maternal samples from each trimester of pregnancy and delivery samples. GenPE is a Colombian study (2000 – 2012, N = 3260 cases, 4331 controls) created to identify maternal and fetal genetic risk variants. Specifically, for this proposal, we will leverage TOPMed X01 funded whole genome sequencing (WGS) on the entire LIFECODES and GenPE cohorts, as well as in-depth multi-omic profiling (metabolic, circulating microparticle proteomic and transcriptomic) on all antepartum plasma samples in matched PE case-control samples within LIFECODES, expected to be available before the grant start date. We propose three specific aims. First, we will perform gene discovery for preeclampsia using common variant, rare variant, gene based and maternal-fetal interaction analyses. Second, we will leverage longitudinal in-depth multi-omic profiling on all antepartum plasma samples in matched PE case- control samples to identify molecular subtypes of PE and link these to known and novel genetic variants. Third, we will test if polygenic risk scores for PE, supplemented by longitudinal molecular and clinical phenotypes, predict maternal morbidity at delivery and future cardiovascular disease. Taken together, analysis of this multi- omics project of PE in TOPMed, together with replication in independent cohorts, will yield novel insights into the etiology of preeclampsia. As adverse pregnancy outcomes dramatically increase the risk of future cardiometabolic disease in affected women, improved mechanistic understanding of pregnancy-related disorders will enhance strategies for improving women’s health and preventing future cardiovascular disease.