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 Eng; Scott 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

doi:10.1016/j.ajhg.2022.04.014

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

Anthropology (Twin Cities)

Research output: Contribution to journal › Article › peer-review

2 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 language	English (US)
Pages (from-to)	1117-1139
Number of pages	23
Journal	American Journal of Human Genetics
Volume	109
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2022.04.014
State	Published - 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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10.1016/j.ajhg.2022.04.014

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Nieves-Colón, M. A., Badillo Rivera, K. M., Sandoval, K., Villanueva Dávalos, V., Enriquez Lencinas, L. E., Mendoza-Revilla, J., Adhikari, K., González-Buenfil, R., Chen, J. W., Zhang, E. T., Sockell, A., Ortiz-Tello, P., Hurtado, G. M., Condori Salas, R., Cebrecos, R., Manzaneda Choque, J. C., Manzaneda Choque, F. P., Yábar Pilco, G. P., Rawls, E., ... Moreno-Estrada, A. (2022). Clotting factor genes are associated with preeclampsia in high-altitude pregnant women in the Peruvian Andes. American Journal of Human Genetics, 109(6), 1117-1139. https://doi.org/10.1016/j.ajhg.2022.04.014

Nieves-Colón, MA, Badillo Rivera, KM, Sandoval, K, Villanueva Dávalos, V, Enriquez Lencinas, LE, Mendoza-Revilla, J, Adhikari, K, González-Buenfil, R, Chen, JW, Zhang, ET, Sockell, A, Ortiz-Tello, P, Hurtado, GM, Condori Salas, R, Cebrecos, R, Manzaneda Choque, JC, Manzaneda Choque, FP, Yábar Pilco, GP, Rawls, E, Eng, C, Huntsman, S, Burchard, E, Ruiz-Linares, A, González-José, R, Bedoya, G, Rothhammer, F, Bortolini, MC, Poletti, G, Gallo, C, Bustamante, CD, Baker, JC, Gignoux, CR, Wojcik, GL & Moreno-Estrada, A 2022, 'Clotting factor genes are associated with preeclampsia in high-altitude pregnant women in the Peruvian Andes', American Journal of Human Genetics, vol. 109, no. 6, pp. 1117-1139. https://doi.org/10.1016/j.ajhg.2022.04.014

@article{518979a33702434291734bcc8c4c0b94,

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

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.",

keywords = "Andean, family trio, GWAS, offspring genome, Peru, preeclampsia, pregnancy, PROZ",

author = "Nieves-Col{\'o}n, {Maria A.} and {Badillo Rivera}, {Keyla M.} and Karla Sandoval and {Villanueva D{\'a}valos}, Vanessa and {Enriquez Lencinas}, {Luis E.} and Javier Mendoza-Revilla and Kaustubh Adhikari and Ram Gonz{\'a}lez-Buenfil and Chen, {Jessica W.} and Zhang, {Elisa T.} and Alexandra Sockell and Patricia Ortiz-Tello and Hurtado, {Gloria Malena} and {Condori Salas}, Ramiro and Ricardo Cebrecos and {Manzaneda Choque}, {Jos{\'e} C.} and {Manzaneda Choque}, {Franz P.} and {Y{\'a}bar Pilco}, {Germ{\'a}n P.} and Erin Rawls and Celeste Eng and Scott Huntsman and Esteban Burchard and Andr{\'e}s Ruiz-Linares and Rolando Gonz{\'a}lez-Jos{\'e} and Gabriel Bedoya and Francisco Rothhammer and Bortolini, {Maria C{\'a}tira} and Giovanni Poletti and Carla Gallo and Bustamante, {Carlos D.} and Baker, {Julie C.} and Gignoux, {Christopher R.} and Wojcik, {Genevieve L.} and Andr{\'e}s Moreno-Estrada",

note = "Funding Information: We extend our deepest gratitude to the people of Puno, Peru who participated in this study at Hospital Regional Manuel Nu{\~n}ez Butr{\'o}n 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 Acu{\~n}a Alonzo from the Instituto Nacional de Antropolog{\'i}a e Historia and Samuel Canizales from the Instituto Nacional de Medicina Gen{\'o}mica 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 Nu{\~n}ez Butr{\'o}n 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 Acu{\~n}a Alonzo from the Instituto Nacional de Antropolog{\'i}a e Historia and Samuel Canizales from the Instituto Nacional de Medicina Gen{\'o}mica 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{\textquoteright}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: {\textcopyright} 2022 American Society of Human Genetics",

year = "2022",

month = jun,

day = "2",

doi = "10.1016/j.ajhg.2022.04.014",

language = "English (US)",

volume = "109",

pages = "1117--1139",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "6",

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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 - 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

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 - family trio

KW - GWAS

KW - offspring genome

KW - Peru

KW - preeclampsia

KW - pregnancy

KW - PROZ

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

SN - 0002-9297

VL - 109

SP - 1117

EP - 1139

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

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

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