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

与人类成瘾中大脑结构异常和药物使用相关的遗传标记

• 批准号: 8891832
• 负责人: Scott J Moeller
• 金额: $ 15.56万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891832
• 关键词: Accounting; Alleles; Atlases; Behavior; Blood specimen; Brain; Brain imaging; Brain region; Candidate Disease Gene; Clinical; Cocaine Dependence; Complex; Corpus striatum structure; Cues; DNA; Data; Diagnosis; Disease; Dorsal; Drug Addiction; Drug usage; Exhibits; Functional disorder; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Goals; Hand; Human; Image; Individual; Intervention; Intervention Studies; Knowledge; Link; Magnetic Resonance Imaging; Maps; Measures; Methaqualone; Modality; Neurobiology; Outcome; Participant; Pharmaceutical Preparations; Pharmacogenetics; Protocols documentation; Psychotic Disorders; Recruitment Activity; Recurrent disease; Relapse; Research; Resources; Rewards; Sampling; Schizophrenia; Self-control as a personality trait; Single Nucleotide Polymorphism; Structural defect; Structure; Sum; Syndrome; System; Testing; Time; Transcript; Urine; addiction; brain behavior; brain morphology; clinically relevant; cocaine use; complement C2a; dopamine transporter; drug relapse; follow-up; gene discovery; genetic approach; genetic information; genetic variant; genome wide association study; gray matter; innovation; insight; interest; neuroimaging; neuropsychiatry; novel; primary outcome; prospective; public health relevance; response; reward processing

 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.

 描述（适用提供）：吸毒成瘾是一种与奖励处理的区域中脑功能和结构缺陷相关的长期传播疾病 和自我控制，表现为抑制和显着属性受损的疾病综合征（IRISA）。该综合征可能会通过在研究和/或加剧添加之前的某些遗传变异进一步调节，这是通过研究单个核苷酸多态性（SNP）对脑和行为的影响的研究证明的。但是，只要单个SNP（例如，Dat1，MAOA）可能仅解释复杂疾病（例如成瘾）中的一小部分行为，因此这种方法在根本上受到限制。为了向前推进该领域，该提案试图实施创新的分析管道，从根本上扩展可能有助于可卡因成瘾的遗传因素菜单（即传统候选基因之外），同时避免了基因组全基因组关联（GWAS）研究（即统计统计功能）的潜在陷阱。分析管道根据以下步骤进行，该步骤将应用于已收集的样本（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）和健康对照组（HC）（HC）在结构灰物质体积（GMV）中的群体差异，可靠，可靠的神经模仿模态； （b）对于那些表现出群体间差异的区域，使用自由利用的大脑图集来绘制和识别基因SNP，共表达网络和特定区域的转录本； （c）使用DNA样品对ICUD和HC中这些相同选择的基因，SNP和网络进行经验测试以验证影响。对于样本2，特别是感兴趣的其他主要结果 是对ICUD中未来药物使用的前瞻性预测，作为4个随访研究课程的一部分，该课程具有多个有效的目标和受试者使用问题。总而言之，这项研究使用一种新型的数据驱动成像遗传学方法来识别ICUD和HC之间先前未表征的遗传差异，而ICUD和HC之间的遗传差异将与脑形态相关，并预测可卡因成瘾中药物相关的结果。