Abstract
Abstract
Study question
The objective of this study is to identify genetic risk factors for recurrent pregnancy loss (RPL) using a trans-ancestry GWAS meta-analysis.
Summary answer
We identified a novel locus near CTNNA2, which links cadherin adhesion receptors to the cytoskeleton regulation of cell adhesion and fetal neurodevelopment to RPL risk.
What is known already
RPL affects approximately 5% of reproductive-age women and is defined as the loss of two or more pregnancies before 24 weeks of gestation. About 50% of RPL cases remain idiopathic, and the genetics of RPL are poorly understood due to challenges in phenotype definition. Additionally, progress in understanding the genetic basis of RPL is limited by its heterogeneity and difficulties in data collection from women with miscarriages. Recent large-scale studies have identified 30 variants reaching genome-wide significance, marking an important step forward in understanding the biology of pregnancy loss. However, only a few of these loci have been successfully replicated.
Study design, size, duration
We conducted ancestry-specific genome-wide association studies (GWAS) of self-reported recurrent miscarriage (RM) in 15,337/136,258 [MOU1] individuals among cases with 2+ miscarriages and controls with no miscarriages of European (discovery), African, White, South/North Asian and East Asian on the UK Biobank data. Additionally, we utilized TOPMed-imputed LUCAR (Lviv Ukrainian Cohort for Advancing Reproductive Health) GWAS from Western Ukraine, which includes 350 women with clinically confirmed idiopathic RPL and 454 controls with at least one healthy child.
Participants/materials, setting, methods
The association analises was performed using BOLT-LMM on the UK Biobank data and SNPTEST on LUCAR study. The GWAS of six datasets (31,024 cases/272,974 controls) were combined into meta-analysis using trans-ancestry meta-regression with MR-MEGA software. We accounted for multiple testing using Bonferroni correction for the number of independent common variant tests in the genome (P-value=3.52 × 10−8).
Main results and the role of chance
We identified a genome-wide significant association at rs4852592-G [IP1] (OR(95%CI)=1.0018(0.976-1.029), P-value= 3.52 × 10−8) located near CTNNA2 gene. The association signal is primarily driven by the largest European-ancestry subset of UKBB. However, we validated (P<0.05) this association at rs4852592 in the East Asian UKBB (P-value=0.0042) and LUCAR (P-value=0.031) studies. Our study reveals novel RM risk locus near CTNNA2 gene, which acts as a link between the cadherin adhesion receptors and the cytoskeleton in regulating cell-cell adhesion, foetal neurodevelopment. It is elevated in the endometrium during implantation, potentially increasing RPL risk, and is nominally associated with gestational age, making it a putative biological target.
Limitations, reasons for caution
The limitation of our study is that the phenotype data in the UK Biobank was self-reported, which may introduce inaccuracies or biases due to recall bias or misclassification of RM. In contrast, the LUCAR study used clinically confirmed idiopathic RPL, enhancing the validity of our findings.
Wider implications of the findings
We report a common variant association for RM near CTNNA2 gene, which suggests a new pathophysiology of this frequent women’s health condition.
Trial registration number
No