Clotting factor genes are associated with preeclampsia in high-altitude pregnant women in the Peruvian Andes

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

AMERICAN JOURNAL OF HUMAN GENETICS

CELL PRESS

Año: 2022 vol. 109 p. 1117 - 1139

0002-9297

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.