Delineating genetic risk to addiction via analysis of 3D chromatin architecture

项目总结： 除阿片类药物外，药物滥用障碍是最紧迫的公共卫生问题之一 美国的危机，吸毒过量是意外死亡的主要原因。20% 尝试海洛因的人会对阿片类药物上瘾。遗传学在定义 这种可变性。据估计，60%的阿片成瘾是遗传的，然而，变种和 定义这种遗传性的基因仍然难以捉摸。正如对疾病所观察到的那样 与精神分裂症一样，全基因组关联研究的样本量和力量都有所增加 可能有助于揭示更多成瘾的遗传基础。然而，识别这些基因座 与上瘾有关只是第一步。为了将这些发现转化为洞察力 可以进一步治疗或预防药物滥用障碍，我们还必须确定 成瘾易感基因座的后果。描绘基因、途径和细胞 由给定的风险基因座改变的表型是一个巨大的挑战，一直是 GWAS结果转化为临床可操作结果的主要障碍。我们建议 利用基因组的三维结构来实现假设驱动的评估 成瘾的遗传风险。这一方法将需要确定顺式监管要素， 控制与组织、细胞类型和环境相关的基因表达 成瘾的病理生理学。我们建议将尸检组织研究与iPS相结合- 衍生的星形胶质细胞、小胶质细胞、少突胶质细胞和多巴胺能神经元提供更深层次的 对导致成瘾易感性的细胞类型和大脑区域的分辨。最后， 我们建议利用iPS衍生的细胞类型来确定可能适合功能性的基因座 研究和利用基因组编辑来调查相关的调节元件的影响 有上瘾的风险。而不是单独分析每个顺式调节元件和SNP， 这种方法将评估控制所有调控元件的遗传变异。 共同的目标基因的表达。这种方法有可能识别新的风险位置 并简化对这些变种致病机制的识别 对上瘾的易感性。

Project Summary: Addition to opioids and substance abuse disorders are one of the most urgent public health crises in the US, with drug overdose being the leading cause of accidental death. 20% of individuals who try heroin become addicted to opioids. Genetics plays a major role in defining this variability. Opioid addiction is estimated to be 60% heritable, however the variants and genes that define this heritability have remained elusive. As has been observed with diseases like schizophrenia, increased sample size and power for Genome Wide Association Studies may help to reveal more of the genetic basis of addiction. However, identifying the loci associated with addiction is only the first step. In order to translate these findings into insights that can further treatment or prevention of substance abuse disorders we must also determine the consequence of addiction susceptibility loci. Delineating the genes, pathways, and cellular phenotypes that are altered by a given risk locus is a substantial challenge and has been the major roadblock in the translation of GWAS results to clinically actionable findings. We propose to utilize 3-dimensional architecture of the genome to enable a hypothesis-driven evaluation of the genetic risk to addiction. This approach will entail identifying the cis-regulatory elements that control gene expression in tissues, cell types and contexts that are relevant to the pathophysiology of addiction. We propose to combine post-mortem tissue studies with iPS- derived astrocytes, microglia, oligodendrocytes and dopaminergic neurons to provide deeper resolution of the cell types and brain regions which contribute to addiction susceptibility. Finally, we propose to utilize the iPS-derived cell types to identify loci may be suitable for functional studies and utilize genome editing to investigate the impact of regulatory elements associated with risk to addiction. Rather than analyze each cis-regulatory element and SNP individually, this approach will evaluate the genetic variation across all regulatory elements that control expression of a shared target gene. This approach has the potential identify new risk loci for addiction and streamline the identification of the mechanism by which these variants contribute to addiction susceptibility.