Cocaine'omics: Genome-wide and Transcriptome-wide Associations With Cocaine Use and Dependence, a GWAS Follow-up Study

We investigated the genetic and transcriptional landscape of cocaine dependence (CD) and chronic cocaine use. We performed and integrated popular genome-wide and transcriptome-wide analyses using data from the largest genome... [ view full abstract ]

We investigated the genetic and transcriptional landscape of cocaine dependence (CD) and chronic cocaine use. We performed and integrated popular genome-wide and transcriptome-wide analyses using data from the largest genome wide association study (GWAS) on CD to date (Gelernter et al. 2014), 3,176 European Americans (EAs), and human post-mortem brain tissue from seven cocaine users and eight drug free controls. First, linkage disequilibrium (LD) score regression analyses was performed and detected a significant genomic heritability of 28% (s.e = 0.14) for CD and gene-based association tests found three novel genes underlying this heritability: the C1QL2, KCTD20 and STK38 genes. Tissue specificity analyses indicated robust enrichment in numerous brain regions, including the hippocampus, sub>adj = 2.02e-06. Therefore using RNA-sequencing (RNA-seq) analyses we performed differential expression and weighted gene covariance network analyses (WGCNA) on post-mortem hippocampal brain tissue from Zhou et al. 2011. Differentially expressed genes or transcripts between chronic cocaine users versus drug free controls were enriched for genes associated with CD (p < 0.05), OR = 1.34, p = 0.031, and were used to find various potential therapeutic compounds for cocaine use/toxicity. Lastly, we found that KCTD20 was a central part of a hippocampal gene network strongly associated with cocaine use and thus, might be contributing to the genetic liability of CD by disrupting intricate gene networks in the brain. Overall, our study elucidates the biological architecture of cocaine use/dependence, proposes various novel therapeutic compounds for cocaine use and includes an alternative framework to validate/provide biological meaning to genome-wide findings.