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Cocaine'omics: Genome‐wide and transcriptome‐wide analyses provide biological insight into cocaine use and dependence
Author(s) -
Huggett Spencer B.,
Stallings Michael C.
Publication year - 2020
Publication title -
addiction biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.445
H-Index - 78
eISSN - 1369-1600
pISSN - 1355-6215
DOI - 10.1111/adb.12719
Subject(s) - genome wide association study , biology , gene , transcriptome , genetics , genome , single nucleotide polymorphism , gene expression profiling , gene expression , genotype
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.