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Genetic insights into the relationship between age at menarche and mental health-related phenotypes
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DOI：10.1192/j.eurpsy.2026.12214.png)
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Abstract
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BackgroundMultiple observational studies have reported associations between age at menarche (AAM) and mental health problems; yet their shared genetic architecture remains poorly characterized.MethodsWe leveraged genome-wide association study summary statistics for AAM and 15 mental health-related phenotypes. We conducted a multi-method integrative analysis encompassing linkage disequilibrium score regression; pleiotropic analysis under the composite null hypothesis; functional mapping and annotation; multi-marker analysis of genomic annotation; pathway enrichment; and bidirectional two-sample Mendelian randomization (MR) to explore shared genetic architecture and potential causal relationships.ResultsOur study identified significant genetic correlations between AAM and eight mental health-related phenotypes (miserableness; fed-up feelings; nervous feelings; ever thought that life is 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 and signaling pathways. Additionally; MR analysis revealed causal associations between AAM and 5 mental health-related phenotypes (mood swings; miserableness; fed-up feelings; and age at which smokers started smoking in former/current smokers).ConclusionsOur study revealed extensive genetic associations between AAM and mental health-related phenotypes; and further explored the potential causal relationships between them. These findings enhance our understanding of the relationship from a genetic perspective and establish a foundation for future research to explore the biological pathways and environmental interactions contributing to these associations.
Keywords:
age at menarche
genetic correlation
mental health
Mendelian randomization
Pleiotropy
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