Ovarian follicles expressed AMH in the antral stage of development in females, and variation in age-specific circulating AMH levels was linked to illness outcomes. However, the physiological processes underpinning these connections between AMH and illness remain largely understood. Researchers did a GWAS meta-analysis by combining summary statistics from a prior 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 analyses accounted for age at blood collection and population stratification, and summary statistics were meta-analyzed using a standard error-weighted method. Subsequently, GWAS variations of genome-wide significance (P<5×10−8) were functionally identified. A gene-based GWAS, pathway analysis, linkage disequilibrium score regression, and Mendelian randomization (MR) analyses were also conducted. At P<5×10−8, investigators detected 4 loci related to AMH levels: the previously reported MCM8 locus and 3 novel 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 connection between AMH levels and age at menopause and single nucleotide polymorphisms (rg=0.82, FDR=0.001). Exploratory 2-sample MR analyses did not support the causal effects of AMH on breast cancer or polycystic ovary syndrome risk. Still, they should be regarded with caution because they might be underpowered, and the validity of genetic instruments could not be thoroughly investigated. Even though this study was twice the most recent GWAS sample size, the statistical power was still inadequate. Consequently, the study group might yet lack the ability to find more genetic variants for AMH and determine the causative consequences on, for instance, breast cancer. In addition, additional research was required to determine whether the AMH gene signal resulted from reduced AMH detection by certain tests as opposed to actual lower circulating AMH levels.
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