Genetic insights into the relationship between age at menarche and mental health-related phenotypes

Background.Multiple observational studies have reported associations between age at menarche (AAM) and mental health problems, yet their shared genetic architecture remains poorly characterized.This study aims to systematically investigate the genetic associations between AAM and mental healthrelated phenotypes.Methods.We leveraged genome-wide association study summary statistics for AAM and fifteen mental health-related phenotypes that were retained after a systematic screening procedure.We conducted a multi-method integrative analysis encompassing linkage disequilibrium score regression, pleiotropic analysis under the composite null hypothesis, functional mapping and annotation, multimarker analysis of genomic annotation, pathway enrichment, and bidirectional two-sample Mendelian randomization (MR) to explore shared genetic architecture and potential causal relationships between AAM and mental health-related phenotypes.Results.Our study identified significant genetic correlations between AAM and 8 mental healthrelated phenotypes (miserableness, fed-up feelings, nervous feelings, ever thought that life not worth living, ever self-harmed, depression, ever smoker, and age started smoking in former smokers).A total of 155 pleiotropic loci, 18 colocalized loci (e.g., 6q16.3) and 203 pleiotropic genes (e.g., LIN28B) were identified.These genes are expressed in multiple regions, including the cerebral cortex and hypothalamus, and are involved in various biological processes (e.g., glutamatergic synapses) and signaling pathways (e.g., mitogen-activated protein kinase signaling pathway).Additionally, MR analysis revealed causal associations between AAM and 5 mental health-related phenotypes (mood swings, miserableness, fed-up feelings, and age started smoking in former/current smokers), while no significant reverse effects of mental health-related phenotypes on AAM were observed.