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

Maria A. Nieves-Colón, Keyla M. Badillo Rivera, Karla Sandoval, Vanessa Villanueva Dávalos, Luis E. Enriquez Lencinas, Javier Mendoza-Revilla, Kaustubh Adhikari, Ram González-Buenfil, Jessica W. Chen, Elisa T. Zhang, Alexandra Sockell, Patricia Ortiz-Tello, Gloria Malena Hurtado, Ramiro Condori Salas, Ricardo Cebrecos, José C. Manzaneda Choque, Franz P. Manzaneda Choque, Germán P. Yábar Pilco, Erin Rawls, Celeste EngScott Huntsman, Esteban Burchard, Andrés Ruiz-Linares, Rolando González-José, Gabriel Bedoya, Francisco Rothhammer, Maria Cátira Bortolini, Giovanni Poletti, Carla Gallo, Carlos D. Bustamante, Julie C. Baker, Christopher R. Gignoux, Genevieve L. Wojcik, Andrés Moreno-Estrada

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1117-1139
Number of pages23
JournalAmerican Journal of Human Genetics
Volume109
Issue number6
DOIs
StatePublished - Jun 2 2022

Bibliographical note

Funding Information:
We extend our deepest gratitude to the people of Puno, Peru who participated in this study at Hospital Regional Manuel Nuñez Butrón and Universidad del Altiplano. We are tremendously grateful to the Mendoza Revilla family, who provided lodging and logistics support in Lima during fieldwork seasons of the technical team. We thank Victor Acuña Alonzo from the Instituto Nacional de Antropología e Historia and Samuel Canizales from the Instituto Nacional de Medicina Genómica of Mexico for providing access to the CANDELA cohort data and Colleen Julian for providing helpful commentary on this manuscript. This work was supported in part by the National Science Foundation (NSF) SBE Postdoctoral Research Fellowship Award No. 1711982 awarded to M.A.N.C.; NSF Graduate Research Fellowship Program Grant No. DGE–1147470 awarded to K.M.B.R. (fellow no. 2014187481); an A.P. Giannini Foundation postdoctoral fellowship, a Stanford Child Health Research Institute postdoctoral award, and a Stanford Dean's Postdoctoral Fellowship awarded to E.T.Z.; the Chan Zuckerberg Biohub Investigator Award to C.D.B.; a Burroughs Welcome Prematurity Initiative Award to J.C.B.; Mexico CONACyT fellowship PNPC 003649 to R.G.B.; and the George Rosenkranz Prize for Health Care Research in Developing Countries, the International Center for Genetic Engineering and Biotechnology (ICGEB, Italy) grant CRP/MEX15-04_EC, and Mexico's CONACYT grant FONCICYT/50/2016, each awarded to A.M.E. Further funding was provided by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, National Institutes of Health, National Heart, Lung, and Blood Institute Awards R01HL117004, R01HL128439, R01HL135156, R01HL141992, National Institute of Environmental Health Sciences Awards R01ES015794, R21ES24844, the National Institute on Minority Health and Health Disparities Awards R01MD010443, and R56MD013312, and the National Human Genome Research Institute Award U01HG009080, each awarded to E.B. In addition, E.B. reports grants from General Medical Sciences, the Tobacco-Related Disease Research Program, and the Food and Drug Administration. J.W.C. is currently a full-time employee at Genentech, Inc. and hold stocks in Roche Holding AG.

Funding Information:
We extend our deepest gratitude to the people of Puno, Peru who participated in this study at Hospital Regional Manuel Nuñez Butrón and Universidad del Altiplano. We are tremendously grateful to the Mendoza Revilla family, who provided lodging and logistics support in Lima during fieldwork seasons of the technical team. We thank Victor Acuña Alonzo from the Instituto Nacional de Antropología e Historia and Samuel Canizales from the Instituto Nacional de Medicina Genómica of Mexico for providing access to the CANDELA cohort data and Colleen Julian for providing helpful commentary on this manuscript. This work was supported in part by the National Science Foundation (NSF) SBE Postdoctoral Research Fellowship Award No. 1711982 awarded to M.A.N.C.; NSF Graduate Research Fellowship Program Grant No. DGE–1147470 awarded to K.M.B.R. (fellow no. 2014187481 ); an A.P. Giannini Foundation postdoctoral fellowship, a Stanford Child Health Research Institute postdoctoral award, and a Stanford Dean’s Postdoctoral Fellowship awarded to E.T.Z.; the Chan Zuckerberg Biohub Investigator Award to C.D.B.; a Burroughs Welcome Prematurity Initiative Award to J.C.B.; Mexico CONACyT fellowship PNPC 003649 to R.G.B.; and the George Rosenkranz Prize for Health Care Research in Developing Countries , the International Center for Genetic Engineering and Biotechnology (ICGEB, Italy) grant CRP/MEX15-04_EC , and Mexico's CONACYT grant FONCICYT/50/2016 , each awarded to A.M.E. Further funding was provided by the Sandler Family Foundation , the American Asthma Foundation , the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, National Institutes of Health , National Heart, Lung, and Blood Institute Awards R01HL117004 , R01HL128439 , R01HL135156 , R01HL141992 , National Institute of Environmental Health Sciences Awards R01ES015794 , R21ES24844 , the National Institute on Minority Health and Health Disparities Awards R01MD010443 , and R56MD013312 , and the National Human Genome Research Institute Award U01HG009080 , each awarded to E.B. In addition, E.B. reports grants from General Medical Sciences , the Tobacco-Related Disease Research Program , and the Food and Drug Administration .

Publisher Copyright:
© 2022 American Society of Human Genetics

Keywords

  • Andean
  • family trio
  • GWAS
  • offspring genome
  • Peru
  • preeclampsia
  • pregnancy
  • PROZ

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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