O-301 Genome-wide association study identified meiotic variant associated with aneuploid pregnancy loss
Authors: Yoshihara H , Otani T , Nishiyama T , Omae Y , Tokunaga K , Fumiko O , Goto S , Kitaori T , Sugiura-Ogasawara M 
Published: June 2022

Abstract

Study question
Which single nucleotide variant (SNVs) are associated with aneuploid pregnancy loss?

Summary answer
We identified a SNV on MEIG1 gene, which are associated with meiosis/spermiogenesis.

What is known already
Recurrent pregnancy loss (RPL) refers to the loss of two or more pregnancies, with a frequency of 5%. Chromosomal abnormalities in embryos are found in 80% of first trimester miscarriages, 86% of which are aneuploid. Recently, embryonic aneuploidy was found to be the most common cause of RPL, with a frequency of 40-50%. Most trisomy miscarriages are of maternal origin, with errors occurring during meiosis of the oocyte. Chromosome segregation abnormalities in oocytes are thought to be an event associated with increasing maternal age, but in addition, maternal genetic causes are thought to contribute.

Study design, size, duration
A Genome wide association study (GWAS) was performed on a clinically well characterized cohort of 189 women with RPL whose previous aborted conceptus was ascertained to be an aneuploid embryo. Samples were mainly collected from 2007 to 2018 mainly at Nagoya City University Hospital. For control samples, we used 1157 samples from the population-based prospective cohorts that included fertile women.

Participants/materials, setting, methods
All patients underwent a systematic examination. Patients with antiphospholipid syndrome, an abnormal chromosome in either partner, or uterine anomaly were excluded. Patients whose previously miscarried POC exhibited triploidy or 45, X were excluded. DNA was isolated from stored EDTA-blood samples and genotyped by Axiom Japonica-array v2659,503 SNVs). For the GWAS, a chi-squared test was applied to a two-by-two contingency table in allele frequency model.

Main results and the role of chance
The mean (SD) ages and number of previous miscarriages of the patients were 36.8 (4.3) and 3.09 (1.13). GWAS data revealed 5 SNVs with suggestive significance (p &lt; 9.46e-06). The SNVs that showed the most significant associations (P = 1.06E-06, OR = 1.72) was located on meiosis/spermiogenesis associated 1 (MEIG1) gene under an allelic model after Bonferroni correction considering the number of analyzed SNVs. The SNV rs7908491 was reported as a splicing QTL in the MEIG1 gene, which is a meiosis/meiosis-associated factor and is plausibly associated with chromosome aneuploidy. This is the first GWAS in patients with RPL caused by aneuploidy.

Limitations, reasons for caution
Since this study was conducted in a single center and had a small sample size, it needs to be replicated in different centers with more subjects and on an international scale. Whole genome imputation analysis will be performed to detect SNVs with more significant associations.

Wider implications of the findings
Our findings demonstrate that a specific genotype of MEIG1 gene can be a risk factor for aneuploid pregnancy loss. The establishment of clinically applicable maternal germ cell markers could identify groups for whom PGT would be more useful or provide patients with counseling that provides prognostic information about pregnancy.

Trial registration number
not applicable