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.

Prioritization of putatively detrimental variants in euploid miscarriages

“…An hemizygous splice site mutation in one male embryo on STAG2 , known in literature for its role in congenital and developmental disorders as well as in cancer 32,34–37 . A missense mutation in TLE4 , a gene that interacts with the genomic region on chromosome 9 genetically associated with miscarriages in a genome-wide study on mothers 9 . TLE4 appears to be a key gene in embryonic development, as it is expressed in both embryonic and extraembryonic tissues where it participates in the Wnt and Notch signalling pathways 43–45 .…”

“…The manually curated list of genes associated with miscarriages (recurrent and spon-taneous) was obtained through a comprehensive search of the published literature. We considered seven studies highlighting the association of genes with miscarriages [Colley et al ., 2019, Fu et al ., 2018, Laisk et al ., 2020, Pereza et al ., 2017, Qiao et al ., 2016, Quintero-Ronderos et al ., 2017, Rull et al ., 2012]. This compendium was further supplemented by genes from curated repositories such as Human Phenotype Ontology (HPO) [Robinson et al, 2008; URL: https://hpo.jax.org/app/browse/term/HP:0200067 last accessed: 1/12/2020 11:01:00 PM] and DisGeNET [Piñero et al, 2015; URL: http://www.disgenet.org/search last accessed: 1/12/2020 11:12:00 PM].…”

“…Both are currently the most accurate methods for the genetic analysis of parental DNA of miscarriages but are not sensitive to small variants, or target only a few coding regions. Using a different approach, the only study so far that tests for genome-wide genetic association in a large cohort of miscarriages is also based only on maternal information [Laisk et al ., 2020]. Depending on the mode of inheritance, the study of the parental genome might be ineffective as there is uncertainty about which parts of the parental genomes are actually inherited by the embryo, and it provides no way to identify de novo mutations.…”

Socio-Epidemiological Factors with Negative Impact on Infant Morbidity, Mortality Rates, and the Occurrence of Birth Defects

“…Generally, 10% of these causes are genetic, another 10% are external (environmental factors), 20–30% are multifactor causes, and in about 50% of the cases, the cause is unknown. According to Laisk et al, about 15% of confirmed pregnancies end in miscarriage, with the causes of these miscarriages being largely due to chromosomal abnormalities inherited in the egg or spermatozoid that occur during egg development or spermatogenesis; other causes may include the action of some toxic factors (smoking, alcohol) after the egg has been fertilized or some maternal diseases [ 9 ]. Some studies show that 40–60% of all fertilized human eggs are lost within the first three weeks post-conception, and 50–60% of miscarried fetuses have chromosomal abnormalities [ 10 ].…”

“…Thus, each organ has its own critical period, and each teratogenic agent has a predilection for a particular organ. The critical period corresponds to embryonic growth and differentiation, which are thought to occur between the 15th and 60th days after fertilization [ 9 ]. If the teratogenic agent acts within the first two weeks, it may directly cause the death of the blastocyst or the embryonic disc, and if it acts after the first 14 days, that agent may cause serious malformations, chromosomal abnormalities, or miscarriage [ 10 ].…”