Nieves-Colón Maria A, Badillo Rivera Keyla M, Sandoval Karla, Villanueva Dávalos Vanessa, Enriquez Lencinas Luis E, Mendoza-Revilla Javier, Adhikari Kaustubh, González-Buenfil Ram, Chen Jessica W, Zhang Elisa T, Sockell Alexandra, Ortiz-Tello Patricia, Hurtado Gloria Malena, Condori Salas Ramiro, Cebrecos Ricardo, Manzaneda Choque José C, Manzaneda Choque Franz P, Yábar Pilco Germán P, Rawls Erin, Eng Celeste, Huntsman Scott, Burchard Esteban, Ruiz-Linares Andrés, González-José Rolando, Bedoya Gabriel, Rothhammer Francisco, Bortolini Maria Cátira, Poletti Giovanni, Gallo Carla, Bustamante Carlos D, Baker Julie C, Gignoux Christopher R, Wojcik Genevieve L, Moreno-Estrada Andrés
Laboratorio Nacional de Genómica para la Biodiversidad (UGA-LANGEBIO), CINVESTAV, Irapuato, Guanajuato 36821, México; School of Human Evolution and Social Change, Arizona State University, Tempe, AZ 85281, USA; Department of Anthropology, University of Minnesota Twin Cities, Minneapolis, MN 55455, USA.
Department of Genetics, Stanford School of Medicine, Stanford, CA 94305, USA.
Am J Hum Genet. 2022 Jun 2;109(6):1117-1139. doi: 10.1016/j.ajhg.2022.04.014. Epub 2022 May 18.
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.
子痫前期是一种妊娠多器官并发症，其特征为突然出现高血压和蛋白尿，是全球早产及孕产妇发病和死亡的主要原因之一。子痫前期的异质性对理解其病因和分子基础构成了挑战。有趣的是，在秘鲁安第斯山脉等高海拔地区，患该病的风险会增加。为了研究高海拔地区人群子痫前期的遗传基础，我们对来自秘鲁普诺（一个海拔超过3800米的城市）的一组子痫前期患者和健康的安第斯家庭（n = 883）的全基因组变异进行了特征分析。我们的研究在当地医院环境中收集了病例对照三联体和二联体的基因组DNA及医疗记录。我们生成了439,314个单核苷酸多态性（SNP）的基因型数据，确定了全球祖先模式，并绘制了遗传变异与子痫前期表型之间的关联图谱。传递不平衡检验（TDT）揭示了与胎盘和血管功能具有生物学重要性的基因附近的变异。在胎儿基因组的13号染色体上发现了最主要的候选区域，其中包含凝血因子基因PROZ、F7和F10。这些发现提供了支持性证据，表明凝血基因内的常见遗传变异在子痫前期中起重要作用。选择扫描揭示了10号染色体上ADAM12基因座周围的一个潜在适应性信号，该信号与妊娠疾病有关。我们在一个未被充分研究的美洲原住民人群中发现了与妊娠生理相关功能途径的关联，这证明了基于家系的研究设计具有更强的效力，并强调了在不同人群中开展基因研究的重要性。
