Cocaine'omics: The Genetic and Neurological Basis of Cocaine Use and Dependence

We investigated the genetic and neurological 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... [ view full abstract ]

We investigated the genetic and neurological 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), 3,370 African Americans (AAs), and human post-mortem brain tissue from 19 cocaine users (all diagnosed with cocaine use disorder) and 17 cocaine free controls. First, we performed a MAGMA gene-based association test and found that the Nicotinamide adenine dinucleotide ubiquinone oxidoreductase subunit Beta 9 (NDUFB9) gene was significantly associated with the genetic predisposition to CD, # SNPs = 174, Z = 4.7917, p = 8.267e-07. Subsequently, we used single cell RNA-sequencing (scRNA-seq) analyses and conducted differential expression and weighted gene covariance network analyses (WGCNA) on post-mortem dorsal-lateral Pre-frontal Cortex neurons from Ribeiro et al. 2017. We detected 133 differentially expressed genes/transcripts between chronic cocaine users versus controls, none of which were genome-wide significant findings from GWAS/gene-based association tests (NDUFB9, FAM53B, C1ql2, KCTD20; _all FDR-BH > 0.34). Using all genes, we created 12 WGCNA networks, which were validated using an external sample of post-mortem brains from cocaine users and controls (Zhou et al. 2011). We found that the blue WGCNA network (# genes = 2,735) was most robustly associated with cocaine use and contained two of the genome-wide findings (NDUFB9, C1ql2) associated with CD via gene-based association tests from AAs and European Americans. The blue gene network was most enriched for KEGG pathways likely involved in the pathophysiology of cocaine use (i.e. GABAergic/Glutamaterigic/Dopamanergic Synapse, cAMP/Ca+ signaling, Alcoholism, Nicotine/Morphine/Cocaine Addiction _all FDR-BH < 0.05). All together, our study elucidates the biological architecture of cocaine use/dependence, proposes an alternative framework to validate/provide biological meaning to genome-wide findings and suggests that one way that the genes predisposing individuals to CD might be disrupting gene networks among the brains of cocaine users.