Mol Psychiatry. 2024 Apr 29. doi: 10.1038/s41380-024-02574-w. Online ahead of print.

ABSTRACT

N6-methyladenosine (m⁶A) methylation regulates gene expression/protein by influencing numerous aspects of mRNA metabolism and contributes to neuropsychiatric diseases. Here, we integrated multi-omics data and genome-wide association study summary data of schizophrenia (SCZ), bipolar disorder (BP), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimer’s disease (AD), and Parkinson’s disease (PD) to reveal the role of m⁶A in neuropsychiatric disorders by using transcriptome-wide association study (TWAS) tool and Summary-data-based Mendelian randomization (SMR). Our investigation identified 86 m⁶A sites associated with seven neuropsychiatric diseases and then revealed 7881 associations between m⁶A sites and gene expressions. Based on these results, we discovered 916 significant m⁶A-gene associations involving 82 disease-related m⁶A sites and 606 genes. Further integrating the 58 disease-related genes from TWAS and SMR analysis, we obtained 61, 8, 7, 3, and 2 associations linking m⁶A-disease, m⁶A-gene, and gene-disease for SCZ, BP, AD, MDD, and PD separately. Functional analysis showed the m⁶A mapped genes were enriched in “response to stimulus” pathway. In addition, we also analyzed the effect of gene expression on m⁶A and the post-transcription effect of m⁶A on protein. Our study provided new insights into the genetic component of m⁶A in neuropsychiatric disorders and unveiled potential pathogenic mechanisms where m⁶A exerts influences on disease through gene expression/protein regulation.

PMID:38684796 | DOI:10.1038/s41380-024-02574-w