RNA profiles reveal signatures of future health and disease in pregnancy

Morten Rasmussen; Mitsu Reddy; Rory Nolan; Joan Camunas-Soler; Arkady Khodursky; Nikolai M. Scheller; David E. Cantonwine; Line Engelbrechtsen; Jia Dai Mi; Arup Dutta; Tiffany Brundage; Farooq Siddiqui; Mainou Thao; Elaine P.S. Gee; Johnny La; Courtney Baruch-Gravett; Mark K. Santillan; Saikat Deb; Shaali M. Ame; Said M. Ali; Melanie Adkins; Mark A. DePristo; Manfred Lee; Eugeni Namsaraev; Dorte Jensen Gybel-Brask; Lillian Skibsted; James A. Litch; Donna A. Santillan; Sunil Sazawal; Rachel M. Tribe; James M. Roberts; Maneesh Jain; Estrid Høgdall; Claudia Holzman; Stephen R. Quake; Michal A. Elovitz; Thomas F. McElrath

doi:10.1038/s41586-021-04249-w

RNA profiles reveal signatures of future health and disease in pregnancy

Morten Rasmussen^*, Mitsu Reddy, Rory Nolan, Joan Camunas-Soler, Arkady Khodursky, Nikolai M. Scheller, David E. Cantonwine, Line Engelbrechtsen, Jia Dai Mi, Arup Dutta, Tiffany Brundage, Farooq Siddiqui, Mainou Thao, Elaine P.S. Gee, Johnny La, Courtney Baruch-Gravett, Mark K. Santillan, Saikat Deb, Shaali M. Ame, Said M. AliMelanie Adkins, Mark A. DePristo, Manfred Lee, Eugeni Namsaraev, Dorte Jensen Gybel-Brask, Lillian Skibsted, James A. Litch, Donna A. Santillan, Sunil Sazawal, Rachel M. Tribe, James M. Roberts, Maneesh Jain, Estrid Høgdall, Claudia Holzman, Stephen R. Quake, Michal A. Elovitz, Thomas F. McElrath

^*Corresponding author for this work

Women & Children's Health

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

117 Citations (Scopus)

Abstract

Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden¹. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method². cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.

Original language	English
Pages (from-to)	422-427
Number of pages	6
Journal	Nature
Volume	601
Issue number	7893
Early online date	5 Jan 2022
DOIs	https://doi.org/10.1038/s41586-021-04249-w
Publication status	Published - 20 Jan 2022

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10.1038/s41586-021-04249-w

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Rasmussen, M., Reddy, M., Nolan, R., Camunas-Soler, J., Khodursky, A., Scheller, N. M., Cantonwine, D. E., Engelbrechtsen, L., Mi, J. D., Dutta, A., Brundage, T., Siddiqui, F., Thao, M., Gee, E. P. S., La, J., Baruch-Gravett, C., Santillan, M. K., Deb, S., Ame, S. M., ... McElrath, T. F. (2022). RNA profiles reveal signatures of future health and disease in pregnancy. Nature, 601(7893), 422-427. https://doi.org/10.1038/s41586-021-04249-w

@article{90ea11fa5fc548f0a68a9eb7590baba5,

title = "RNA profiles reveal signatures of future health and disease in pregnancy",

abstract = "Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden1. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method2. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.",

author = "Morten Rasmussen and Mitsu Reddy and Rory Nolan and Joan Camunas-Soler and Arkady Khodursky and Scheller, {Nikolai M.} and Cantonwine, {David E.} and Line Engelbrechtsen and Mi, {Jia Dai} and Arup Dutta and Tiffany Brundage and Farooq Siddiqui and Mainou Thao and Gee, {Elaine P.S.} and Johnny La and Courtney Baruch-Gravett and Santillan, {Mark K.} and Saikat Deb and Ame, {Shaali M.} and Ali, {Said M.} and Melanie Adkins and DePristo, {Mark A.} and Manfred Lee and Eugeni Namsaraev and Gybel-Brask, {Dorte Jensen} and Lillian Skibsted and Litch, {James A.} and Santillan, {Donna A.} and Sunil Sazawal and Tribe, {Rachel M.} and Roberts, {James M.} and Maneesh Jain and Estrid H{\o}gdall and Claudia Holzman and Quake, {Stephen R.} and Elovitz, {Michal A.} and McElrath, {Thomas F.}",

note = "Funding Information: Acknowledgements We thank all women who donated blood samples and made this study possible. This research was conducted using specimens and data collected, stored and managed by INSIGHT, LIFECODES, The Women{\textquoteright}s Health Tissue, Pregnancy Outcomes and Community Health (POUCH), Prenatal Exposures and Preeclampsia Prevention (PEPP), Global Alliance to Prevent Prematurity and Stillbirth (GAPPS), Pemba Pregnancy and Newborn Discovery Cohort (PPNDC) and Roskilde biorepositories. We thank the Precia Group for introducing and coordinating with key study collaborators. Samples from the INSIGHT study were collected with support from Tommy{\textquoteright}s Charity (no. 1060508), the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy{\textquoteright}s and St Thomas{\textquoteright} National Health Service Foundation Trust, the Rosetrees Trust (charity no. 298582) (M303-CD1) and an NIHR Doctoral Research Fellowship (DRF-2013-06-171) to N.L. Hezelgrave. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Research reported in this publication was supported by UI BioShare, the enterprise biospecimen management system supported by the University of Iowa{\textquoteright}s Carver College of Medicine, Holden Comprehensive Cancer Center and Institute for Clinical and Translational Science. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = jan,

day = "20",

doi = "10.1038/s41586-021-04249-w",

language = "English",

volume = "601",

pages = "422--427",

journal = "Nature",

issn = "0028-0836",

publisher = "Springer Nature",

number = "7893",

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Rasmussen, M, Reddy, M, Nolan, R, Camunas-Soler, J, Khodursky, A, Scheller, NM, Cantonwine, DE, Engelbrechtsen, L, Mi, JD, Dutta, A, Brundage, T, Siddiqui, F, Thao, M, Gee, EPS, La, J, Baruch-Gravett, C, Santillan, MK, Deb, S, Ame, SM, Ali, SM, Adkins, M, DePristo, MA, Lee, M, Namsaraev, E, Gybel-Brask, DJ, Skibsted, L, Litch, JA, Santillan, DA, Sazawal, S, Tribe, RM, Roberts, JM, Jain, M, Høgdall, E, Holzman, C, Quake, SR, Elovitz, MA & McElrath, TF 2022, 'RNA profiles reveal signatures of future health and disease in pregnancy', Nature, vol. 601, no. 7893, pp. 422-427. https://doi.org/10.1038/s41586-021-04249-w

TY - JOUR

T1 - RNA profiles reveal signatures of future health and disease in pregnancy

AU - Rasmussen, Morten

AU - Reddy, Mitsu

AU - Nolan, Rory

AU - Camunas-Soler, Joan

AU - Khodursky, Arkady

AU - Scheller, Nikolai M.

AU - Cantonwine, David E.

AU - Engelbrechtsen, Line

AU - Mi, Jia Dai

AU - Dutta, Arup

AU - Brundage, Tiffany

AU - Siddiqui, Farooq

AU - Thao, Mainou

AU - Gee, Elaine P.S.

AU - La, Johnny

AU - Baruch-Gravett, Courtney

AU - Santillan, Mark K.

AU - Deb, Saikat

AU - Ame, Shaali M.

AU - Ali, Said M.

AU - Adkins, Melanie

AU - DePristo, Mark A.

AU - Lee, Manfred

AU - Namsaraev, Eugeni

AU - Gybel-Brask, Dorte Jensen

AU - Skibsted, Lillian

AU - Litch, James A.

AU - Santillan, Donna A.

AU - Sazawal, Sunil

AU - Tribe, Rachel M.

AU - Roberts, James M.

AU - Jain, Maneesh

AU - Høgdall, Estrid

AU - Holzman, Claudia

AU - Quake, Stephen R.

AU - Elovitz, Michal A.

AU - McElrath, Thomas F.

N1 - Funding Information: Acknowledgements We thank all women who donated blood samples and made this study possible. This research was conducted using specimens and data collected, stored and managed by INSIGHT, LIFECODES, The Women’s Health Tissue, Pregnancy Outcomes and Community Health (POUCH), Prenatal Exposures and Preeclampsia Prevention (PEPP), Global Alliance to Prevent Prematurity and Stillbirth (GAPPS), Pemba Pregnancy and Newborn Discovery Cohort (PPNDC) and Roskilde biorepositories. We thank the Precia Group for introducing and coordinating with key study collaborators. Samples from the INSIGHT study were collected with support from Tommy’s Charity (no. 1060508), the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy’s and St Thomas’ National Health Service Foundation Trust, the Rosetrees Trust (charity no. 298582) (M303-CD1) and an NIHR Doctoral Research Fellowship (DRF-2013-06-171) to N.L. Hezelgrave. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Research reported in this publication was supported by UI BioShare, the enterprise biospecimen management system supported by the University of Iowa’s Carver College of Medicine, Holden Comprehensive Cancer Center and Institute for Clinical and Translational Science. Publisher Copyright: © 2022, The Author(s).

PY - 2022/1/20

Y1 - 2022/1/20

N2 - Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden1. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method2. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.

AB - Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden1. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method2. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.

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U2 - 10.1038/s41586-021-04249-w

DO - 10.1038/s41586-021-04249-w

M3 - Article

AN - SCOPUS:85122294056

SN - 0028-0836

VL - 601

SP - 422

EP - 427

JO - Nature

JF - Nature

IS - 7893

ER -

RNA profiles reveal signatures of future health and disease in pregnancy

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