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.
PY - 2020/11/25
Y1 - 2020/11/25
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.
U2 - 10.1038/s41467-020-19742-5
DO - 10.1038/s41467-020-19742-5
M3 - Article (Academic Journal)
C2 - 33239672
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 5980 (2020)
ER -