The genetic architecture of sporadic and multiple consecutive miscarriage

Triin Laisk; Ana Luiza G. Soares; Teresa Ferreira; Jodie N. Painter; Jenny C. Censin; Samantha Laber; Jonas Bacelis; Chia Yen Chen; Maarja Lepamets; Kuang Lin; Siyang Liu; Iona Y. Millwood; Avinash Ramu; Jennifer Southcombe; Marianne S. Andersen; Ling Yang; Christian M. Becker; Anders D. Børglum; Scott D. Gordon; Jonas Bybjerg-Grauholm; Øyvind Helgeland; David M. Hougaard; Xin Jin; Stefan Johansson; Julius Juodakis; Christiana Kartsonaki; Viktorija Kukushkina; Penelope A. Lind; Andres Metspalu; Grant W. Montgomery; Andrew P. Morris; Ole Mors; Preben B. Mortensen; Pål R. Njølstad; Merete Nordentoft; Dale R. Nyholt; Margaret Lippincott; Stephanie Seminara; Andres Salumets; Harold Snieder; Krina Zondervan; Thomas Werge; Zhengming Chen; Donald F. Conrad; Bo Jacobsson; Liming Li; Nicholas G. Martin; Benjamin M. Neale; Rasmus Nielsen; Robin G. Walters; Ingrid Granne; Sarah E. Medland; Reedik Mägi; Deborah A. Lawlor; Cecilia M. Lindgren

doi:10.1038/s41467-020-19742-5

The genetic architecture of sporadic and multiple consecutive miscarriage

Triin Laisk, Ana Luiza G. Soares, Teresa Ferreira, Jodie N. Painter, Jenny C. Censin, Samantha Laber, Jonas Bacelis, Chia Yen Chen, Maarja Lepamets, Kuang Lin, Siyang Liu, Iona Y. Millwood, Avinash Ramu, Jennifer Southcombe, Marianne S. Andersen, Ling Yang, Christian M. Becker, Anders D. Børglum, Scott D. Gordon, Jonas Bybjerg-GrauholmØyvind Helgeland, David M. Hougaard, Xin Jin, Stefan Johansson, Julius Juodakis, Christiana Kartsonaki, Viktorija Kukushkina, Penelope A. Lind, Andres Metspalu, Grant W. Montgomery, Andrew P. Morris, Ole Mors, Preben B. Mortensen, Pål R. Njølstad, Merete Nordentoft, Dale R. Nyholt, Margaret Lippincott, Stephanie Seminara, Andres Salumets, Harold Snieder, Krina Zondervan, Thomas Werge, Zhengming Chen, Donald F. Conrad, Bo Jacobsson, Liming Li, Nicholas G. Martin, Benjamin M. Neale, Rasmus Nielsen, Robin G. Walters, Ingrid Granne, Sarah E. Medland, Reedik Mägi, Deborah A. Lawlor, Cecilia M. Lindgren

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Abstract

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10⁻⁸, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10⁻⁸, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10⁻⁹, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10⁻⁸, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

Original language	English (US)
Article number	5980
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19742-5
State	Published - Dec 2020
Externally published	Yes

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.1038/s41467-020-19742-5

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Laisk, T., Soares, A. L. G., Ferreira, T., Painter, J. N., Censin, J. C., Laber, S., Bacelis, J., Chen, C. Y., Lepamets, M., Lin, K., Liu, S., Millwood, I. Y., Ramu, A., Southcombe, J., Andersen, M. S., Yang, L., Becker, C. M., Børglum, A. D., Gordon, S. D., ... Lindgren, C. M. (2020). The genetic architecture of sporadic and multiple consecutive miscarriage. Nature communications, 11(1), Article 5980. https://doi.org/10.1038/s41467-020-19742-5

Laisk, T, Soares, ALG, Ferreira, T, Painter, JN, Censin, JC, Laber, S, Bacelis, J, Chen, CY, Lepamets, M, Lin, K, Liu, S, Millwood, IY, Ramu, A, Southcombe, J, Andersen, MS, Yang, L, Becker, CM, Børglum, AD, Gordon, SD, Bybjerg-Grauholm, J, Helgeland, Ø, Hougaard, DM, Jin, X, Johansson, S, Juodakis, J, Kartsonaki, C, Kukushkina, V, Lind, PA, Metspalu, A, Montgomery, GW, Morris, AP, Mors, O, Mortensen, PB, Njølstad, PR, Nordentoft, M, Nyholt, DR, Lippincott, M, Seminara, S, Salumets, A, Snieder, H, Zondervan, K, Werge, T, Chen, Z, Conrad, DF, Jacobsson, B, Li, L, Martin, NG, Neale, BM, Nielsen, R, Walters, RG, Granne, I, Medland, SE, Mägi, R, Lawlor, DA & Lindgren, CM 2020, 'The genetic architecture of sporadic and multiple consecutive miscarriage', Nature communications, vol. 11, no. 1, 5980. https://doi.org/10.1038/s41467-020-19742-5

@article{0d5c9298f386449b999e7f4a5ac4a4ec,

title = "The genetic architecture of sporadic and multiple consecutive miscarriage",

abstract = "Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10−8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10−8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10−9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10−8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.",

author = "Triin Laisk and Soares, {Ana Luiza G.} and Teresa Ferreira and Painter, {Jodie N.} and Censin, {Jenny C.} and Samantha Laber and Jonas Bacelis and Chen, {Chia Yen} and Maarja Lepamets and Kuang Lin and Siyang Liu and Millwood, {Iona Y.} and Avinash Ramu and Jennifer Southcombe and Andersen, {Marianne S.} and Ling Yang and Becker, {Christian M.} and B{\o}rglum, {Anders D.} and Gordon, {Scott D.} and Jonas Bybjerg-Grauholm and {\O}yvind Helgeland and Hougaard, {David M.} and Xin Jin and Stefan Johansson and Julius Juodakis and Christiana Kartsonaki and Viktorija Kukushkina and Lind, {Penelope A.} and Andres Metspalu and Montgomery, {Grant W.} and Morris, {Andrew P.} and Ole Mors and Mortensen, {Preben B.} and Nj{\o}lstad, {P{\aa}l R.} and Merete Nordentoft and Nyholt, {Dale R.} and Margaret Lippincott and Stephanie Seminara and Andres Salumets and Harold Snieder and Krina Zondervan and Thomas Werge and Zhengming Chen and Conrad, {Donald F.} and Bo Jacobsson and Liming Li and Martin, {Nicholas G.} and Neale, {Benjamin M.} and Rasmus Nielsen and Walters, {Robin G.} and Ingrid Granne and Medland, {Sarah E.} and Reedik M{\"a}gi and Lawlor, {Deborah A.} and Lindgren, {Cecilia M.}",

note = "Funding Information: T.L. is supported by European Commission Horizon 2020 research and innovation program (project WIDENLIFE, grant number 692065); Estonian Ministry of Education and Research (grants IUT34-16, PUT IUT20-60, PUTJD726, and MOBTP155); Enterprise Estonia (grant EU49695). J.C.C. is funded by the Oxford Medical Research Council Doctoral Training Partnership (Oxford MRC DTP) and the Nuffield Department of Clinical Medicine, University of Oxford. S.L. is supported by a Novo Nordisk Postdoctoral Fellowship run in partnership with the University of Oxford. C.M.L. is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds, Oxford, NIHR Oxford Biomedical Research Centre, Oxford, Widenlife and NIH (5P50HD028138-27). D.F.C. is supported by grants from the National Institutes of Health (R01HD078641, R01MH101810, and P51OD011092). R.M. is funded by Estonian Ministry of Education and Research (grant PRG687). T.F. is supported by the NIHR Biomedical Research Centre, Oxford. S.E.M. and J.N.P. were supported by NHMRC applications APP1103623 and APP1084325. Partners HealthCare Biobank is supported by NHGRI grant U01HG008685. This study was funded by EU H2020 grant 692145, Estonian Research Council Grant IUT20-60, IUT24-6, and European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED and 2014-2020.4.01.16-0125. Data analyses were carried out in part in the High-Performance Computing Center of University of Tartu. This study was funded by The Lundbeck Foundation, Denmark. This research has been conducted using the Danish National Biobank resource, supported by the Novo Nordisk Foundation. Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. Financial support was provided by the Wellcome Trust Core Award Grant Number 203141/Z/16/ Z. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank the study subjects for their valuable participation. We thank the twins and their families for their participation in the QIMR study. We acknowledge with appreciation all women who participated in the QIMR endometriosis study. We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The authors wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centers delivering data to Lifelines, and all the study participants. A full list of acknowledgements is provided in the Supplementary Note 2. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

doi = "10.1038/s41467-020-19742-5",

language = "English (US)",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - The genetic architecture of sporadic and multiple consecutive miscarriage

AU - Laisk, Triin

AU - Soares, Ana Luiza G.

AU - Ferreira, Teresa

AU - Painter, Jodie N.

AU - Censin, Jenny C.

AU - Laber, Samantha

AU - Bacelis, Jonas

AU - Chen, Chia Yen

AU - Lepamets, Maarja

AU - Lin, Kuang

AU - Liu, Siyang

AU - Millwood, Iona Y.

AU - Ramu, Avinash

AU - Southcombe, Jennifer

AU - Andersen, Marianne S.

AU - Yang, Ling

AU - Becker, Christian M.

AU - Børglum, Anders D.

AU - Gordon, Scott D.

AU - Bybjerg-Grauholm, Jonas

AU - Helgeland, Øyvind

AU - Hougaard, David M.

AU - Jin, Xin

AU - Johansson, Stefan

AU - Juodakis, Julius

AU - Kartsonaki, Christiana

AU - Kukushkina, Viktorija

AU - Lind, Penelope A.

AU - Metspalu, Andres

AU - Montgomery, Grant W.

AU - Morris, Andrew P.

AU - Mors, Ole

AU - Mortensen, Preben B.

AU - Njølstad, Pål R.

AU - Nordentoft, Merete

AU - Nyholt, Dale R.

AU - Lippincott, Margaret

AU - Seminara, Stephanie

AU - Salumets, Andres

AU - Snieder, Harold

AU - Zondervan, Krina

AU - Werge, Thomas

AU - Chen, Zhengming

AU - Conrad, Donald F.

AU - Jacobsson, Bo

AU - Li, Liming

AU - Martin, Nicholas G.

AU - Neale, Benjamin M.

AU - Nielsen, Rasmus

AU - Walters, Robin G.

AU - Granne, Ingrid

AU - Medland, Sarah E.

AU - Mägi, Reedik

AU - Lawlor, Deborah A.

AU - Lindgren, Cecilia M.

N1 - Funding Information: T.L. is supported by European Commission Horizon 2020 research and innovation program (project WIDENLIFE, grant number 692065); Estonian Ministry of Education and Research (grants IUT34-16, PUT IUT20-60, PUTJD726, and MOBTP155); Enterprise Estonia (grant EU49695). J.C.C. is funded by the Oxford Medical Research Council Doctoral Training Partnership (Oxford MRC DTP) and the Nuffield Department of Clinical Medicine, University of Oxford. S.L. is supported by a Novo Nordisk Postdoctoral Fellowship run in partnership with the University of Oxford. C.M.L. is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds, Oxford, NIHR Oxford Biomedical Research Centre, Oxford, Widenlife and NIH (5P50HD028138-27). D.F.C. is supported by grants from the National Institutes of Health (R01HD078641, R01MH101810, and P51OD011092). R.M. is funded by Estonian Ministry of Education and Research (grant PRG687). T.F. is supported by the NIHR Biomedical Research Centre, Oxford. S.E.M. and J.N.P. were supported by NHMRC applications APP1103623 and APP1084325. Partners HealthCare Biobank is supported by NHGRI grant U01HG008685. This study was funded by EU H2020 grant 692145, Estonian Research Council Grant IUT20-60, IUT24-6, and European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED and 2014-2020.4.01.16-0125. Data analyses were carried out in part in the High-Performance Computing Center of University of Tartu. This study was funded by The Lundbeck Foundation, Denmark. This research has been conducted using the Danish National Biobank resource, supported by the Novo Nordisk Foundation. Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. Financial support was provided by the Wellcome Trust Core Award Grant Number 203141/Z/16/ Z. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank the study subjects for their valuable participation. We thank the twins and their families for their participation in the QIMR study. We acknowledge with appreciation all women who participated in the QIMR endometriosis study. We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The authors wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centers delivering data to Lifelines, and all the study participants. A full list of acknowledgements is provided in the Supplementary Note 2. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12

Y1 - 2020/12

N2 - Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10−8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10−8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10−9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10−8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

AB - Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10−8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10−8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10−9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10−8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

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JF - Nature communications

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The genetic architecture of sporadic and multiple consecutive miscarriage

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