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Abstract
We investigated the genetic and molecular architecture of cocaine dependence (CD)
and cocaine use by integrating genome-/transcriptome-wide analyses. To prioritize
candidates for follow-up investigation, we also sought to translate gene expression
findings across species. Using data from the largest genome-wide association study
(GWAS) of CD to date (n = 3176, 74% with CD), we assessed genomic heritability, gene-based
associations, and tissue enrichment. We detected a significant single-nucleotide polymorphism
heritability of 28% for CD and identified three genes (two loci) underlying this predisposition:
the C1qL2 (complement component C1 q like 2), KCTD20 (potassium channel tetramerization
domain containing 20), and STK38 (serine/threonine kinase 38) genes. Tissue enrichment
analyses indicated robust enrichment in numerous brain regions, including the hippocampus.
We used postmortem human hippocampal RNA-sequencing data from previous study (n = 15,
seven chronic cocaine users) to follow up genome-wide results and to identify differentially
expressed genes/transcripts and gene networks underlying cocaine use. Cross-species
analyses utilized hippocampal gene expression from a mouse model of cocaine use. Differentially
expressed genes/transcripts in humans were enriched for the genes nominally associated
with CD via GWAS (P < 0.05) and for differentially expressed genes in the hippocampus
of cocaine-exposed mice. We identified KCTD20 as a central component of a hippocampal
gene network strongly associated with human cocaine use, and this gene network was
conserved in the mouse hippocampus. We outline a framework to map and translate genome-wide
findings onto tissue-specific gene expression, which provided biological insight into
cocaine use/dependence.