Preeclampsia is a multi-organ complication of pregnancy characterized by sudden hypertension and proteinuria that is among the leading causes of preterm delivery and maternal morbidity and mortality worldwide. The heterogeneity of preeclampsia poses a challenge for understanding its etiology and molecular basis. Intriguingly, risk for the condition increases in high-altitude regions such as the Peruvian Andes. To investigate the genetic basis of preeclampsia in a population living at high altitude, we characterized genome-wide variation in a cohort of preeclamptic and healthy Andean families (n = 883) from Puno, Peru, a city located above 3,800 meters of altitude. Our study collected genomic DNA and medical records from case-control trios and duos in local hospital settings. We generated genotype data for 439,314 SNPs, determined global ancestry patterns, and mapped associations between genetic variants and preeclampsia phenotypes. A transmission disequilibrium test (TDT) revealed variants near genes of biological importance for placental and blood vessel function. The top candidate region was found on chromosome 13 of the fetal genome and contains clotting factor genes PROZ, F7, and F10. These findings provide supporting evidence that common genetic variants within coagulation genes play an important role in preeclampsia. A selection scan revealed a potential adaptive signal around the ADAM12 locus on chromosome 10, implicated in pregnancy disorders. Our discovery of an association in a functional pathway relevant to pregnancy physiology in an understudied population of Native American origin demonstrates the increased power of family-based study design and underscores the importance of conducting genetic research in diverse populations.

先兆子痫是妊娠的多器官并发症，其特征是突发性高血压和蛋白尿，是全球早产和孕产妇发病率和死亡率的主要原因之一。先兆子痫的异质性对理解其病因学和分子基础提出了挑战。有趣的是，在秘鲁安第斯山脉等高海拔地区，患这种疾病的风险会增加。为了调查生活在高海拔地区的人群中先兆子痫的遗传基础，我们对来自海拔 3,800 米以上的秘鲁普诺市的一组先兆子痫和健康的安第斯家庭 (n = 883) 的全基因组变异进行了表征。我们的研究从当地医院环境中的病例对照三重奏和二重奏中收集了基因组 DNA 和医疗记录。我们生成了 439,314 个 SNP 的基因型数据，确定了全球血统模式，并绘制了遗传变异与先兆子痫表型之间的关联。传递不平衡试验 (TDT) 揭示了对胎盘和血管功能具有生物学重要性的基因附近的变异。最高候选区域位于胎儿基因组的 13 号染色体上，包含凝血因子基因PROZ、F7和F10。这些发现提供了支持证据，证明凝血基因中的常见遗传变异在先兆子痫中起着重要作用。选择扫描揭示了 10 号染色体上ADAM12基因座周围的潜在适应性信号，与妊娠疾病有关。我们在未被充分研究的美洲原住民人群中发现了与妊娠生理学相关的功能通路的关联，这表明基于家庭的研究设计的作用越来越大，并强调了在不同人群中进行基因研究的重要性。