Journal Article

The genetic architecture of sporadic and multiple consecutive miscarriage

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

2020

Overview

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. Miscarriage affects around 15% of clinically confirmed pregnancies. Here the authors carry out a large genome-wide association study for sporadic and multiple consecutive miscarriage and suggest links with placental biology.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/43 / 631/208/205/2138 / 692/699/2732/1577 / Abortion, Habitual - epidemiology / Abortion, Habitual - genetics / Abortion, Habitual - physiopathology / Abortion, Spontaneous - epidemiology / Abortion, Spontaneous - genetics / Abortion, Spontaneous - physiopathology / Adult / Aged / Biobanks / Biology / Case-Control Studies / Correlation analysis / Datasets as Topic / Female / Gene Frequency / Genetic analysis / Genetic diversity / Genetic Predisposition to Disease / Genome-wide association studies / Genome-Wide Association Study / Genomes / Gynaecology, Obstetrics and Reproductive Medicine / Gynekologi, obstetrik och reproduktionsmedicin / Heritability / Humanities and Social Sciences / Humans / Inheritance Patterns / Medical History Taking / Middle Aged / Miscarriage / multidisciplinary / Placenta / Placenta - physiopathology / Polymorphism, Single Nucleotide / Pregnancy / Science / Science (multidisciplinary) / White People - genetics / Young Adult