Women’s AMH levels can be attributed to three different genes

Ovarian follicles expressed AMH in the antral developmental stage in women, and variation in age-specific circulating AMH levels was associated with disease outcome. However, the physiological processes that support these links between AMH and disease are still widely understood. Researchers performed a GWAS meta-analysis by combining summary statistics from a previous AMH GWAS with GWAS data from 3,705 additional women from 3 cohorts. They included information from a total of 7,049 premenopausal women of European descent. Across cohorts, the median age of research participants ranged from 15.3 to 48 years. Several ELISA techniques analyzed serum and plasma samples for circulating AMH concentrations. Study-specific analyzes took into account age at blood collection and population stratification, and summary statistics were meta-analyzed using a standard error-weighted method. Subsequent GWAS variations of genome-wide significance (P<5 × 10-8) was functionally identified. A gene-based GWAS, pathway analysis, coupling imbalance score regression and Mendelian randomization (MR) analyzes were also performed. On P<5 × 10-8, investigators discovered 4 loci related to AMH levels: the previously reported MCM8 locus and 3 new signals in or near AMH, TEX41 and CDCA7. The strongest signal was an AMH gene missense variation. Most prioritized genes at the remaining 3 loci involved cell cycle regulation. Genetic correlation analysis revealed a high positive correlation between AMH levels and age at menopause and single nucleotide polymorphisms (rg = 0.82, FDR = 0.001). Exploratory 2-sample MRI analyzes did not support the causal effects of AMH on the risk of breast cancer or polycystic ovary syndrome. Nevertheless, they should be considered with caution because they may be underpowered and the validity of genetic instruments could not be thoroughly investigated. Although this study was twice the most recent GWAS sample size, the statistical power was still insufficient. Therefore, the study group may not yet lack the ability to find more genetic variants for AMH and determine the causal consequences of e.g. breast cancer. In addition, further research was needed to determine if the AMH gene signal was the result of reduced AMH detection in certain tests as opposed to actual lower circulating AMH levels.


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