Genetic markers associated with brain structural abnormalities and drug use in human addiction

 描述(申请人提供)：毒瘾是一种慢性复发性疾病，与奖赏处理基础区域的大脑功能和结构缺陷有关 和自我控制，表现为反应抑制和显著归因受损(IRSA)的恶性综合征。单核苷酸多态(SNPs)对大脑和行为的影响的研究证明，这种综合征可能会受到在成瘾之前和/或加剧成瘾之前和/或加剧的特定遗传变异的进一步调节。然而，这种方法从根本上是有限的，因为单个SNPs(例如，DAT1，MAOA)可能只解释成瘾等复杂疾病中的一小部分行为。为了推动这一领域的发展，这项提议寻求实施一种创新的分析管道，从根本上扩大可能导致可卡因成瘾的遗传因素的菜单(即，超出传统候选基因)，同时避免全基因组关联(GWAS)研究的潜在陷阱(即，统计能力不足)。分析流程将按照以下步骤进行，这些步骤将应用于已经收集的样本(样本1)和新的正在进行的样本(样本2)：(A)探测可卡因使用障碍(ICUD)患者和健康对照组(HC)在结构性灰质体积(GMV)方面的群体差异，这是一种可靠和可靠的神经成像模式；(B)对于那些显示组间差异的区域，使用免费可用的脑图谱来绘制和识别基因SNP、共表达网络和区域特定转录本；以及(C)使用DNA样本对这些相同的选定基因、SNPs和iCUD和HC中的网络进行实证测试，以验证影响。具体地说，对于样本2，另一个感兴趣的主要结果 是对iCUD未来药物使用的前瞻性预测，作为4次后续研究的一部分，使用多个有效的客观和主观药物使用探测器进行评估。总之，这项研究使用了一种新的数据驱动的成像遗传学方法来识别iCUD和HC之间以前未描述的遗传差异，这些差异将被用来与大脑形态相关，并预测可卡因成瘾的药物相关结果。

 DESCRIPTION (provided by applicant): Drug addiction is a chronically relapsing disease associated with deficits in brain function and structure in regions that underlie reward processing and self-control, manifesting as a pernicious syndrome of impaired response inhibition and salience attribution (iRISA). This syndrome is likely further modulated by select genetic variations that precede and/or exacerbate the addiction, evidenced by studies that have examined the influence of single nucleotide polymorphisms (SNPs) on brain and behavior. However, this approach is fundamentally limited insofar as individual SNPs (e.g., DAT1, MAOA) are likely to explain only a small portion of behavior in complex disorders such as addiction. To move the field forward, this proposal seeks to implement an innovative analysis pipeline to fundamentally expand upon the menu of genetic factors that may contribute to cocaine addiction (i.e., beyond traditional candidate genes) while simultaneously avoiding the potential pitfalls of genome-wide association (GWAS) studies (i.e., insufficient statistical power). The analysis pipeline proceeds according to the following steps, which will be applied to an already-collected sample (Sample 1) and a new, ongoing sample (Sample 2): (A) probing for group differences between individuals with cocaine use disorder (iCUD) and healthy controls (HC) in structural gray matter volume (GMV), a reliable and robust neuroimaging modality; (B) for those regions exhibiting between-group differences, using a freely-available brain Atlas to map and identify gene SNPs, coexpression networks, and region-specific transcripts; and (C) using DNA samples for empirical testing of these same select genes, SNPs, and networks in iCUD and HC for verification of influence. For Sample 2 specifically, an additional primary outcome of interest is the prospective prediction of future drug use in iCUD, assessed as part of 4 follow-up study sessions with multiple, valid objective and subjective drug use probes. In sum, this study uses a novel data-driven imaging genetics approach to identify previously uncharacterized genetic differences between iCUD and HC, which in turn will be used to correlate with brain morphology and predict drug-relevant outcomes in cocaine addiction.