TY - JOUR
T1 - Clotting factor genes are associated with preeclampsia in high-altitude pregnant women in the Peruvian Andes
AU - Nieves-Colón, Maria A.
AU - Badillo Rivera, Keyla M.
AU - Sandoval, Karla
AU - Villanueva Dávalos, Vanessa
AU - Enriquez Lencinas, Luis E.
AU - Mendoza-Revilla, Javier
AU - Adhikari, Kaustubh
AU - González-Buenfil, Ram
AU - Chen, Jessica W.
AU - Zhang, Elisa T.
AU - Sockell, Alexandra
AU - Ortiz-Tello, Patricia
AU - Hurtado, Gloria Malena
AU - Condori Salas, Ramiro
AU - Cebrecos, Ricardo
AU - Manzaneda Choque, José C.
AU - Manzaneda Choque, Franz P.
AU - Yábar Pilco, Germán P.
AU - Rawls, Erin
AU - Eng, Celeste
AU - Huntsman, Scott
AU - Burchard, Esteban
AU - Ruiz-Linares, Andrés
AU - González-José, Rolando
AU - Bedoya, Gabriel
AU - Rothhammer, Francisco
AU - Bortolini, Maria Cátira
AU - Poletti, Giovanni
AU - Gallo, Carla
AU - Bustamante, Carlos D.
AU - Baker, Julie C.
AU - Gignoux, Christopher R.
AU - Wojcik, Genevieve L.
AU - Moreno-Estrada, Andrés
N1 - Publisher Copyright:
© 2022 American Society of Human Genetics
PY - 2022/6/2
Y1 - 2022/6/2
N2 - 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.
AB - 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.
KW - Andean
KW - GWAS
KW - PROZ
KW - Peru
KW - family trio
KW - offspring genome
KW - preeclampsia
KW - pregnancy
UR - http://www.scopus.com/inward/record.url?scp=85131126132&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85131126132&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2022.04.014
DO - 10.1016/j.ajhg.2022.04.014
M3 - Article
C2 - 35588731
AN - SCOPUS:85131126132
SN - 0002-9297
VL - 109
SP - 1117
EP - 1139
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -