MGA loss-of-function variants cause premature ovarian insufficiency
Shuyan Tang, Ting Guo, Chengcheng Song, Lingbo Wang, Jun Zhang, Aleksandar Rajkovic, Xiaoqi Lin, Shiling Chen, Yujun Liu, Weidong Tian, Bangguo Wu, Shixuan Wang, Wenwen Wang, Yunhui Lai, Ao Wang, Shuhua Xu, Li Jin, Hanni Ke, Shidou Zhao, Yan Li, Yingying Qin, Feng Zhang, Zi-Jiang Chen
Shuyan Tang, Ting Guo, Chengcheng Song, Lingbo Wang, Jun Zhang, Aleksandar Rajkovic, Xiaoqi Lin, Shiling Chen, Yujun Liu, Weidong Tian, Bangguo Wu, Shixuan Wang, Wenwen Wang, Yunhui Lai, Ao Wang, Shuhua Xu, Li Jin, Hanni Ke, Shidou Zhao, Yan Li, Yingying Qin, Feng Zhang, Zi-Jiang Chen
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Research Article Genetics Reproductive biology

MGA loss-of-function variants cause premature ovarian insufficiency

Abstract

Although premature ovarian insufficiency (POI), a common cause of female infertility and subfertility, has a well-established hereditary component, the genetic factors currently implicated in POI account for only a limited proportion of cases. Here, using an exome-wide, gene-based case-control analysis in a discovery cohort comprising 1,027 POI cases and 2,733 ethnically matched women controls from China, we found that heterozygous loss-of-function (LoF) variants of MAX dimerization protein (MGA) were significantly enriched in the discovery cohort, accounting for 2.6% of POI cases, while no MGA LoF variants were found in the matched control females. Further exome screening was conducted in 4 additional POI cohorts (2 from China and 2 from the United States) for replication studies, and we identified heterozygous MGA LoF variants in 1.0%, 1.4%, 1.0%, and 1.0% of POI cases, respectively. Overall, a total of 37 distinct heterozygous MGA LoF variants were discovered in 38 POI cases, accounting for approximately 2.0% of the total 1,910 POI cases analyzed in this study. Accordingly, Mga+/− female mice were subfertile, exhibiting shorter reproductive lifespan and decreased follicle number compared with WT, mimicking the observed phenotype in humans. Our findings highlight the essential role of MGA deficiency for impaired female reproductive ability.

Authors

Shuyan Tang, Ting Guo, Chengcheng Song, Lingbo Wang, Jun Zhang, Aleksandar Rajkovic, Xiaoqi Lin, Shiling Chen, Yujun Liu, Weidong Tian, Bangguo Wu, Shixuan Wang, Wenwen Wang, Yunhui Lai, Ao Wang, Shuhua Xu, Li Jin, Hanni Ke, Shidou Zhao, Yan Li, Yingying Qin, Feng Zhang, Zi-Jiang Chen

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Figure 1

Identification of MGA as a POI-associated gene in the discovery cohort.

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Identification of MGA as a POI-associated gene in the discovery cohort. ...
(A) Genetic analysis pipeline of exome-wide gene burden tests using WES data in the discovery POI cohort and matched female controls. (B) Gene-based Q-Q plot of P values in the discovery stage based on 2-sided Fisher’s exact tests. Expected P values are obtained from 1,000 permutations. The burden of variants adhering to 3 variant types, namely LoF, damaging missense, and synonymous, was tested for each of the 19,199 genes. Points on the plot are color coded according to the variant types indicated in the legend. The inflation factors (λ) for the 3 variant types are 1.08, 1.03, and 1.00, respectively. The red dashed line represents the Bonferroni’s correction threshold of 2.6 × 10–6 (0.05/19,199) for each variant type. (C) Manhattan plot illustrating the association between genes with LoF variants and POI from the discovery cohort. The –log10(observed P values) are plotted against the genetic position for each analyzed gene. The red dashed line represents the Bonferroni’s correction threshold, and the blue dashed line indicates a suggestive significance threshold of 0.005. The genes achieving the suggestive significance threshold are labeled.