Genome-Wide Screening for Risk Loci of Idiopathic Recurrent Miscarriage in a Han Chinese Population: A Pilot Study

Wang, Li; Wang, Zeng Chan; Xie, Chengzhi; Liu, Xiaofeng; Yang, Mingliang

doi:10.1177/1933719110364248

Cited by 23 publications

(18 citation statements)

References 60 publications

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“…None of these variants were genomewide significant in either the sporadic or recurrent miscarriage analysis, and only 14 (4.2%) and 11 (3%) were nominally significant (P<0.05) in the respective analyses ( Supplementary Table 4). Two genome-wide linkage scans, one of 44 recurrent miscarriage cases and 44 controls and the other of 38 sibling pairs affected by idiopathic recurrent miscarriage reported loci on 6q27, 9q33.1, Xp22.1 23 and 3p12.2, 9p22.1 and 11q13.4 14 as associated with idiopathic recurrent miscarriage but none of the recurrent or sporadic miscarriage associations identified in our much larger analysis overlap with these previously reported regions.…”

supporting

confidence: 51%

The genetic architecture of sporadic and recurrent miscarriage

Laisk

Soares

Ferreira³

et al. 2019

Preprint

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Miscarriage is a common complex trait that affects 10-25% of clinically confirmed pregnancies1,2. Here we present the first large-scale genetic association analyses with 69,118 cases from five different ancestries for sporadic miscarriage and 750 cases of European ancestry for recurrent miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association on chromosome 13 (rs146350366, minor allele frequency (MAF) 1.2%,Pmeta=3.2×-8(CI) 1.2-1.6) for sporadic miscarriage in our European ancestry meta-analysis (50,060 cases and 174,109 controls), located nearFGF9involved in pregnancy maintenance3and progesterone production4. Additionally, we identified three genome-wide significant associations for recurrent miscarriage, including a signal on chromosome 9 (rs7859844, MAF=6.4%,Pmeta=1.3×-8in controlling extravillous trophoblast motility5. We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability and, genetic correlation analyses. Our results implicate that miscarriage etiopathogenesis is partly driven by genetic variation related to gonadotropin regulation, placental biology and progesterone production.

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supporting

confidence: 51%

The genetic architecture of sporadic and recurrent miscarriage

Laisk

Soares

Ferreira³

et al. 2019

Preprint

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“…This has restricted their efficient use in clinical studies. Genome-wide scan-based studies have been reported, although they have not reached the classical accepted statistical threshold for significance and have apparently failed to identify specific genes [12,13]. Such failure to identify RSA aetiological genes might be explained by the fact that reproduction's inherent complexity theoretically implies that mutations in hundreds of candidate genes may be responsible for the phenotype [10,14].…”

Section: Introductionmentioning

confidence: 99%

Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans

et al. 2016

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Recurrent spontaneous abortion (RSA) is a common cause of infertility, but previous attempts at identifying RSA causative genes have been relatively unsuccessful. Such failure to describe RSA aetiological genes might be explained by the fact that reproductive phenotypes should be considered as quantitative traits resulting from the intricate interaction of numerous genetic, epigenetic and environmental factors. Here, we studied an interspecific recombinant congenic strain (IRCS) of Mus musculus from the C57BL6/J strain of mice harbouring an approximate 5 Mb DNA fragment from chromosome 13 from Mus spretus mice (66H-MMU13 strain), with a high rate of embryonic resorption (ER). Transcriptome analyses of endometrial and placental tissues from these mice showed a deregulation of many genes associated with the coagulation and inflammatory response pathways. Bioinformatics approaches led us to select Foxd1 as a candidate gene potentially related to ER and RSA. Sequencing analysis of Foxd1 in the 66H-MMU13 strain, and in 556 women affected by RSA and 271 controls revealed non-synonymous sequence variants. In vitro assays revealed that some led to perturbations in FOXD1 transactivation properties on promoters of genes having key roles during implantation/placentation, suggesting a role of this gene in mammalian implantation processes.

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“…These differentially expressed genes were found to be associated with defective cell growth, thus suggesting their implication in implantation failure in women with unexplained RM. Wang et al performed a case-control and genome-wide study, and analyzed 430 polymorphic microsatellite markers [62]. Three loci -6q27, 9q33.1 and Xp22.11 -were found to be significantly associated with RM.…”

Section: Genome-wide Studiesmentioning

confidence: 98%

Genetic factors influencing recurrent pregnancy loss: lessons learnt from recent studies

Dasgupta

Aruna

Reddy³

2012

Expert Review of Obstetrics & Gynecology

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Recurrent spontaneous abortions, also known as recurrent miscarriages (RMs), of unknown etiology provide a fundamental basis to understand the processes of embryogenesis and implantation. It is a distressing condition for the couple as well as the treating clinician. RM presents a varied etiology with a different combination of factors playing a role in its manifestation. Despite recent advances in the investigation and management of RM, a relatively large proportion of the cases remain idiopathic. An abortion is any loss before 20 gestational weeks [1]. RM is defined as the loss of two or more consecutive pregnancies spontaneously before the 24th week of gestation [2]. The modern definition, however, is the spontaneous loss of two or more consecutive pregnancies before 20 weeks of gestation [3,4]. A large number of pathological factors have been attributed to the etiology of RM, including chromosomal abnormalities, anatomic defects, immunological factors, endocrine disturbances and thrombophilia, to name a few. This has inevitably led to an understanding of the molecular genetic basis of these etiological factors, primarily with regard to the immunological and thrombophilic factors. Consequently, there has been a constant rise in the number of genetic association studies in different populations, including those from India. However, a definite conclusion on the molecular genetic etiology of RM is still lacking. In this article, we present a comprehensive review of such molecular genetic association studies based on the underlying genetic factors of three major etiologic categories in RM: immunological factors, thrombophilic factors and endocrine factors. Etiology of RM Genetic disordersChromosomal abnormalities occur in 50% of all conception products from first-trimester miscarriages, 5% of late pregnancy miscarriages and 0.5% of live births. These chromosomal anomalies could be due to aneuploidy (monosomy, trisomy and polyploidy) or structural abnormalities, such as translocations and inversions. Approximately 3% of cytogenetically abnormal conceptions are due to structural rearrangements [5]. Anatomical disordersAnatomical investigations are normally performed by hysterosalpingography, hysteroscopy or ultrasound scans. However, hysteroscopy and advanced imaging techniques (3D ultrasonography and MRI) and laparoscopy (if necessary) Recurrent miscarriage (RM) is the loss of three or more consecutive pregnancies before the 24th week of gestation. RM occurs chiefly owing to either a problem with the pregnancy or the environment where it implants and further development occurs. A large number of pathological factors have been attributed to the etiology of RM. A number of genetic association studies in different populations, including that of India, have been conducted, yet with no definite conclusions. This review analyzes various genetic association studies that have been conducted based on the underlying immunological, thrombophilic and endocrine factors in RM, and outlines the salient features of the findings an...

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Genome-Wide Screening for Risk Loci of Idiopathic Recurrent Miscarriage in a Han Chinese Population: A Pilot Study

Cited by 23 publications

References 60 publications

The genetic architecture of sporadic and recurrent miscarriage

The genetic architecture of sporadic and recurrent miscarriage

Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans

Genetic factors influencing recurrent pregnancy loss: lessons learnt from recent studies

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