Prioritized RNA modification enzymes as risk genes for bipolar I disorder and schizophrenia

Enzyme-mediated RNA modifications provide a versatile and dynamic regulatory layer in brain development and neural function, orchestrated by over 100 RNA modification proteins (RMPs). A systematic assessment of contribution by common genetic variants in RMP genes to psychiatric disorders has been lacking. Here we curated 123 human RMPs—corresponding to 31 modification types on 6 RNA biotypes—and tested their genetic associations with 16 disorders from the Psychiatric Genomics Consortium (PGC), using GWAS annotation, gene-based association testing, transcriptome-wide association studies (TWAS), Summary data-based Mendelian randomization (SMR), Bayesian colocalization, and gene-set enrichment analysis. As a set of genes, the RMPs did not show significant disease association; at individual gene levels, candidate RMPs were linked to bipolar I disorder (BIPI) and schizophrenia (SCZ). NSUN2 , a cytosine-5 methyltransferase, was consistently supported by multiple analyses as a risk gene for BIPI and SCZ. Additional candidates, including NSUN6 , TYW5 , TRMT61A , QTRT1 , and MRM1 , also showed significant gene-level associations. All significant SMR associations were negative (β _SMR  < 0), consistent with a downregulation pattern observed in patient brains. A cross-gene comparison showed that NSUN2 and TYW5 exhibit comparable signal enrichment to established risk genes for BIPI and SCZ, respectively. These results warrant future investigations for the roles of specific RMPs in complex mental disorders.