Variations and expression features of CYP2D6 contribute to schizophrenia risk

Abstract

ObjectiveGenome-wide association studies (GWAS) have successfully identified 145 loci implicated in schizophrenia (SCZ). However, the underlying mechanisms remain largely unknown.\n\nMethodsHere, we analyze 1,479 RNA-seq data from 13 postmortem brain regions in combination with their genotype data and identify SNPs that are associated with expression throughout the genome by dissecting expression features to genes (eGene) and exon-exon junctions (eJunction). Then, we co-localize eGene and eJunction with SCZ GWAS using SMR and mapping. Multiple ChIP-seq data and DNA methylation data generated from brain were used for identifying the causative variants. Finally, we used a hypothesis-free (no SCZ risk loci considered) enrichment analysis to determine implicated pathways.\n\nResultsWe identified 171 genes and eight splicing junctions located within four genes (SNX19, ARL6IP4, APOPT1 and CYP2D6) that potentially contribute to SCZ susceptibility. Among the genes, CYP2D6 is significantly associated with SCZ SNPs in both eGene and eJunction across the 13 brain regions. In-depth examination of the CYP2D6 region revealed that a non-synonymous single nucleotide variant (SNV) rs16947 is strongly associated with a higher abundance of CYP2D6 exon 3 skipping junctions. While we found rs133377 and two other SNPs in high linkage disequilibrium (LD) with rs16947 (r2 = 0.9539), histone acetylation analysis showed they are located within active transcription start sites. Furthermore, our data-driven enrichment analysis showed CYP2D6 is significantly involved in drug metabolism of tamoxifen, codeine and citalopram.\n\nConclusionsOur study facilitates an understanding of the genetic architecture of SCZ and provides new drug targets.