Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado.
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado.
Addict Biol. 2020 Mar;25(2):e12719. doi: 10.1111/adb.12719. Epub 2019 Feb 8.
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.
我们通过整合全基因组/转录组分析来研究可卡因依赖（CD）和可卡因使用的遗传和分子结构。为了优先选择后续调查的候选者，我们还试图在不同物种间转化基因表达研究结果。利用迄今为止最大的可卡因依赖全基因组关联研究（GWAS）的数据（n=3176，74%为 CD），我们评估了基因组遗传率、基于基因的关联和组织富集。我们检测到 CD 的显著单核苷酸多态性遗传率为 28%，并确定了三个基因（两个基因座）是这种易感性的基础：C1qL2（补体成分 C1q 样 2）、KCTD20（钾通道四聚化结构域包含 20）和 STK38（丝氨酸/苏氨酸激酶 38）基因。组织富集分析表明，在许多大脑区域，包括海马体，存在丰富的表达。我们使用之前研究的死后人类海马体 RNA 测序数据（n=15，7 名慢性可卡因使用者）来跟进全基因组结果，并鉴定可卡因使用的差异表达基因/转录本和基因网络。跨物种分析利用了可卡因使用的小鼠模型中的海马体基因表达数据。人类中的差异表达基因/转录本在通过 GWAS 与 CD 关联的基因中显著富集（P<0.05），并且在可卡因暴露的小鼠海马体中差异表达的基因中也显著富集。我们确定 KCTD20 是与人类可卡因使用强烈相关的海马体基因网络的核心组成部分，并且该基因网络在小鼠海马体中是保守的。我们概述了一个将全基因组发现映射和转化为组织特异性基因表达的框架，为可卡因使用/依赖提供了生物学见解。
