The genetic architecture of sporadic and multiple consecutive miscarriage
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Published:2020-11-25
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Laisk TriinORCID, Soares Ana Luiza G.ORCID, Ferreira Teresa, Painter Jodie N.ORCID, Censin Jenny C.ORCID, Laber Samantha, Bacelis JonasORCID, Chen Chia-Yen, Lepamets Maarja, Lin Kuang, Liu Siyang, Millwood Iona Y., Ramu Avinash, Southcombe Jennifer, Andersen Marianne S., Yang Ling, Becker Christian M.ORCID, Børglum Anders D.ORCID, Gordon Scott D.ORCID, Bybjerg-Grauholm JonasORCID, Helgeland Øyvind, Hougaard David M.ORCID, Jin Xin, Johansson StefanORCID, Juodakis JuliusORCID, Kartsonaki Christiana, Kukushkina Viktorija, Lind Penelope A.ORCID, Metspalu AndresORCID, Montgomery Grant W.ORCID, Morris Andrew P.ORCID, Mors Ole, Mortensen Preben B., Njølstad Pål R.ORCID, Nordentoft Merete, Nyholt Dale R.ORCID, Lippincott Margaret, Seminara Stephanie, Salumets Andres, Snieder HaroldORCID, Zondervan KrinaORCID, Werge ThomasORCID, Chen ZhengmingORCID, Conrad Donald F., Jacobsson BoORCID, Li LimingORCID, Martin Nicholas G.ORCID, Neale Benjamin M.ORCID, Nielsen RasmusORCID, Walters Robin G.ORCID, Granne Ingrid, Medland Sarah E.ORCID, Mägi Reedik, Lawlor Deborah A.ORCID, Lindgren Cecilia M.ORCID
Abstract
AbstractMiscarriage 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference74 articles.
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