33. GENETIC REGULATION OF HUMAN BRAIN RNA EDITING IN EAST ASIAN

RNA editing in the human brain exhibits a highly dynamic and complex regulatory landscape. With the rapid advancement of high-throughput sequencing technologies, many studies have focused on using edQTLs to explain GWAS signals. However, current studies are largely centered on European populations and primarily investigate genetic regulation at the level of individual editing sites. This approach overlooks the population-specific nature of RNA editing. Moreover, multiple studies have shown that RNA editing sites often occur in clusters and may be subject to coordinated regulation. To address those gaps, we aimed to construct the first large-scale RNA editing regulatory map in East Asians and proposed a novel concept of regional editing QTLs (redQTLs), treating regional average editing levels as an endophenotype for QTL analysis. We conducted whole-genome and transcriptome sequencing on 546 samples from the DLPFC of East Asian individuals. For cross-population comparison, we also included 429 matched DNA and RNA sequencing samples from the European BrainGVEx cohort. RNA editing sites were identified by integrating novel candidates from REDItools2 with known sites from public databases. We then performed edQTL mapping to assess the genetic regulation of RNA editing and compared the results with those from the European cohort. Co-localization analyses were conducted to fine-map SCZ GWAS signals. Finally, based on the average RNA editing level within each region, we performed regional RNA editing quantitative trait locus (redQTL) mapping to explore their coordinated genetic regulation, which reflects the biologically clustered nature of RNA editing. (1) We constructed the first large-scale map of genetic regulation of RNA editing in the East Asian population. 18,648 high-confidence RNA editing sites were identified in this study, and 504,500 edQTLs were identified by QTL analysis, of which 473,637 were East Asian–specific. (2) The edQTL repetition rate within the same population was higher than that between different populations(π1(EUR-EAS) = 0.73 and π1(EAS-EAS) = 0.86). Population-specific edQTL differences were mainly driven by allele frequency variation. Shared signals showed consistent regulatory directions. (3) Colocalization analysis identified 20 schizophrenia-associated editing sites in East Asians, including four novel candidate genes (MPHOSPH9, CSMD1, MFSD13A, KCNIP4), and the sites chr7_137067935 and chr7_137067938 were shared risk sites for both populations, with DGKI and UBE2D3 being the shared risk genes. (4) A total of 3,096 RNA editing regions and 136,286 redQTL were identified in the East Asian population by combining editing correlation, spatial proximity, and other factors. (5) redQTL showed a higher cross-population sharing rate compared to edQTL (from 12.8% to 39.7%). Notably, in the European population, we identified a novel SCZ-colocalized editing region (chr7_38764259_ld) that did not show significant signals in the edQTL analysis. This study constructed the first large-scale brain edQTL map in East Asian populations. It advances our understanding of population-specific mechanisms underlying RNA editing. Through colocalization analysis with neuropsychiatric disorders such as schizophrenia (SCZ), we identified four East Asian–specific SCZ-colocalized genes that have not been reported in previous studies. Additionally, our redQTL analysis further explores the coordinated genetic regulation of RNA editing.