Integrative omics of preeclampsia in TOPMED and maternal cardiovascular health

子痫前期(PE)是妊娠20周后出现的新发高血压和蛋白尿，是一种 由胎盘介导的严重妊娠特有疾病，影响所有妊娠的5%。女性与 既往的PE患者一生中患心血管疾病的风险增加2-4倍，包括缺血性心脏病和 卒中。PE的潜在病因仍然知之甚少；因此，预测和治疗 选择仍然有限。PE有相当大的可遗传成分，估计有55%-60%，母体和 胎儿贡献率，估计分别为30-35%和20%。对PE遗传学的理解取得了进展 落后于其他疾病的原因：两个基因组(母体和胎儿)的参与、疾病的异质性、 产科表型被排除在许多大型队列研究之外，缺乏足够的PE收集 识别遗传风险基因座的能力的样本大小。除了遗传学，使用其他基因组学策略对PE进行剖析 已经确定了疾病之前的转录组、蛋白质组和代谢组改变。然而，PE队列 在同一个人身上有多个基因组学，缺乏表型良好的个体。要应对这些挑战， 为了加深对PE病理生理学的理解，我们建议利用TOPMed数据在波士顿-哥伦比亚 协作性不良妊娠结局研究--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&GT；3000例妊娠，152例PE病例)，每三个月的母亲样本 妊娠和分娩样本。GenPE是一项哥伦比亚研究(2000-2012，N=3260例，4331例对照) 创建的目的是识别母体和胎儿的遗传风险变异。具体地说，对于这个提案，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) 在ALL上进行深入的多组学分析(代谢、循环微粒蛋白质组和转录) LIFECODES内匹配的PE病例对照样本中的产前血浆样本，预计可用 在拨款开始日期之前。我们提出了三个具体目标。首先，我们将为您进行基因发现 使用常见变异、罕见变异、基于基因和母婴相互作用分析的先兆子痫。第二, 我们将对匹配的PE病例的所有产前血浆样本进行纵向深入的多组分析- 对照样本，以确定PE的分子亚型，并将这些亚型与已知和新的遗传变异联系起来。第三, 我们将测试PE的多基因风险评分，并辅之以纵向分子和临床表型， 预测产妇分娩时的发病率和未来的心血管疾病。综上所述，分析这多个- TOPMed中的PE组学项目，以及在独立队列中的复制，将产生对 先兆子痫的病因学。因为不良妊娠结局大大增加了未来的风险 受影响妇女的心脏代谢性疾病，提高了对妊娠相关机制的理解 精神障碍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.