rs2251219

This functional genomic study identified 16 transcription factor binding-disrupting SNPs across reported bipolar disorder (BD) GWAS loci and elucidated their regulatory mechanisms. Using eQTL analysis, CRISPR/Cas9 editing, and functional assays, the authors demonstrated that rs10896081 disrupts PBX3 binding to regulate PACS1 and YIF1A expression, and that rs3862386 similarly regulates PACS1 expression. PACS1 overexpression affected dendritic spine density in neurons, suggesting a mechanistic link between these functional SNPs and BD risk through regulation of genes involved in synaptic function.

This comprehensive review examines the genomics of schizophrenia and pharmacogenomics of antipsychotic drugs, synthesizing evidence on over 200 genes associated with psychotic disorders. The authors discuss five categories of genes relevant to antipsychotic response: disease-associated genes, mechanism-of-action genes, drug metabolism genes (particularly CYP2D6, CYP2C19, CYP2C9, CYP3A4), drug transporter genes, and pleiotropic genes. The review details pharmacogenomic profiles of 20+ antipsychotic drugs and demonstrates significant ethnic and interindividual variation in drug metabolism phenotypes, with examples including CYP2D6 extensive metabolizers (55.71% of population), intermediate metabolizers (34.7%), poor metabolizers (2.28%), and ultra-rapid metabolizers (7.31%).