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

<title>Abstract</title> <p> 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). <italic>NSUN2</italic> , a cytosine-5 methyltransferase, was consistently supported by multiple analyses as a risk gene for BIPI and SCZ. Additional candidates, including <italic>NSUN6</italic> , <italic>TYW5</italic> , <italic>TRMT61A</italic> , <italic>QTRT1</italic> , and <italic>MRM1</italic> , also showed significant gene-level associations. All significant SMR associations were negative (β _SMR  &lt; 0), consistent with a downregulation pattern observed in patient brains. A cross-gene comparison showed that <italic>NSUN2</italic> and <italic>TYW5</italic> 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. </p>