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: 9059066
• 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/9059066
• 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; Health; 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; imaging genetics; innovation; insight; interest; neuroimaging; neuropsychiatric disorder; novel; predict clinical outcome; primary outcome; prospective; 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（由申请人提供）：药物成瘾是一种慢性复发性疾病，与奖励处理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着性归因受损的恶性综合征（iRISA），这种综合征可能会受到先于和/或加剧成瘾的特定遗传变异的进一步调节，这一点已通过研究单一因素的影响进行了证明。然而，这种方法从根本上来说是有限的，因为单个 SNP（例如 DAT1、MAOA）可能只能解释复杂疾病中的一小部分行为。为了推动该领域的发展，该提案旨在实施一种创新的分析流程，从根本上扩展可能导致可卡因成瘾的遗传因素（即超越传统的候选基因），同时避免基因组的潜在陷阱。广泛关联 (GWAS) 研究（即统计能力不足），分析流程按照以下步骤进行，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）： （一个）探索可卡因使用障碍 (iCUD) 和健康对照 (HC) 个体在结构灰质体积 (GMV) 方面的群体差异，这是一种可靠且稳健的神经影像学模式；(B) 对于那些表现出组间差异的区域，使用自由-可用的大脑图谱来绘制和识别基因 SNP、共表达网络和区域特异性转录本；(C) 使用 DNA 样本对 iCUD 和 HC 中的这些相同选定基因、SNP 和网络进行实证测试，以验证影响。特别是对于样本 2，还有一个额外的主要关注结果 是对 iCUD 中未来药物使用的前瞻性预测，作为 4 个后续研究会议的一部分，使用多个有效的客观和主观药物使用探针进行评估。 总之，本研究使用一种新颖的数据驱动成像遗传学方法来识别以前未表征的药物。 iCUD 和 HC 之间的遗传差异，反过来将用于与大脑形态相关并预测可卡因成瘾的药物相关结果。