Intermediate Phenotypes for Alcoholism and Whole Genome Linkage Scan

酗酒的中间表型和全基因组连锁扫描

• 批准号: 8559254
• 负责人: David Goldman
• 金额: $ 4.94万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8559254
• 关键词: Affect; Affinity; African American; Alcohol dependence; Alcoholism; American Indians; Anxiety; Anxiety Disorders; Binding; Biological; Brain; Buffers; CRH gene; Candidate Disease Gene; Caucasians; Caucasoid Race; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 5; Collaborations; Complex; Corpus striatum structure; DRD2 gene; Data; Data Set; Disease; Distal; Dopamine; Electroencephalogram; Electroencephalography; Event-Related Potentials; Exons; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Variation; Genome; Genotype; HTR3A gene; Haplotypes; Heritability; High Prevalence; Image; Individual; Low Prevalence; Measures; Mediating; Mental disorders; Michigan; National Institute of Drug Abuse; Nicotine; Oxytocin; Phenotype; Population; Positron-Emission Tomography; Protein Isoforms; RNA Splicing; Rest; Role; Sampling; Scanning; Signal Transduction; Stress; Substance Addiction; Substance abuse problem; Universities; Variant; Woman; addiction; alcohol use disorder; anti social; biological adaptation to stress; corticotropin releasing factor-binding protein; emotional stimulus; men; pediatric trauma; protein aminoacid sequence; protein folding; receptor; relating to nervous system; response; reward processing; serotonin receptor; stress related disorder; suicidal behavior; trait

The heritability of alcoholism is 40-60% in both men and women however, as in other complex psychiatric diseases it has proved difficult to identify causative genes. Intermediate phenotypes are associated biological traits that may be influenced by variation at fewer genes and may mediate different aspects of the disease. The intermediate phenotypes for alcoholism that we are studying include dimensional anxiety (harm avoidance), resting EEG phenotypes and event-related potentials (ERPs). We have three large electrophysiological intermediate phenotype datasets: 247 U.S. Caucasians, 365 Plains American Indians with a high prevalence of alcoholism and 198 Southeastern American Indians with a low prevalence of alcoholism. In collaboration with Dr Zubietta from the University of Michigan and Dr Stein from NIDA we are also studying imaging data (fMRI and positron emission tomography (PET)) as an intermediate phenotype for addiction-related phenotypes. A whole genome linkage scan in the Plains Indian sample did not identify a linkage signal for alcoholism. However, there was a convergence of linkage peaks for alpha, beta and theta EEG power on chromosome (chr) 5 with LOD scores of 3.5. The gene for corticotropin releasing hormone binding protein (CRHBP) was located at the apex of the convergent linkage peaks. CRHBP is implicated in stress and addiction. Subsequent analyses showed that CRHBP SNPs and haplotypes were significantly associated with alpha EEG power in the Plains Indians and also the U.S. Caucasians. Moreover, the same CRHBP SNPs were significantly associated with anxiety disorders in the Plains Indians and alcohol use disorders in the U.S. Caucasians (Enoch et al, 2008). These results suggest a likely role for CRHBP in stress-related disorders including alcoholism. Indeed, we have recently shown that in a sample of African American men with substance dependence, the same distal CRHBP SNPs predicted suicidal behavior in those individuals who had been exposed to severe childhood trauma (Roy et al, 2012). CRHBP is buffered from adjacent genes by several haplotype blocks indicating that a functional locus is likely to reside within this gene or its environs. We have demonstrated the presence of an alternative CRHBP isoform in brain in which the terminal exon is spliced out in favor of two alternative exons resulting in a change in peptide sequence that might affect protein folding and stability resulting in altered CRH binding affinity. Functional studies are currently underway. A linkage peak for theta EEG power with a LOD score of 3.2 was found on chr 22. There were suggestive peaks (LOD = 2.2 to 2.5) on chrs 4, 10 and 11. There are three candidate genes at the apex of the linkage peak on chr 11: serotonin receptors 3A and 3B (HTR3A and HTR3B) and DRD2. We found a significant association between HTR3B and EEG alpha power in both the Plains Indians and U.S. Caucasians and with antisocial alcoholism in Finnish Caucasians (Ducci et al, 2009). Moreover, in a sample of African American men with substance abuse, we found that a functional HTR3B SNP rs1176744 was associated with alcohol dependence (Enoch et al, 2011). Our studies have shown that intermediate phenotypes are particularly useful for identifying genes for alcoholism in populations with a high prevalence of this disease. Recent collaborative studies with Dr Zubietta have revealed that in women only, genetic variation in the oxytocin gene is associated with stress-induced dopamine activation (measured by PET), a vulnerability factor for alcoholism (Love et al, 2012). Also, variation in the CRHR1 gene that encodes the stress-response CRH1 receptor was associated with differences in neural responses (measured by fMRI) to emotional stimuli (Hsu et al, 2012) that may indicate vulnerability to stress-related disorders including alcoholism. Finally, in a collaboration with Dr Stein's group from NIDA we have shown that nicotine and COMT Val158Met genotype regulate activation (measured by fMRI) in a cortico-striatal network during reward processing (Lee et al, submitted). Formerly titled "Genetic studies of the electroencephalogram and event-related potentials" and "Genetic studies of EEG and ERP traits related to alcoholism".

酒精中毒的遗传率在男性和女性中均为 40-60%，然而，与其他复杂的精神疾病一样，事实证明很难识别致病基因。中间表型是相关的生物学特征，可能受到较少基因变异的影响，并且可能介导疾病的不同方面。我们正在研究的酗酒中间表型包括维度焦虑（伤害避免）、静息脑电图表型和事件相关电位（ERP）。我们拥有三个大型电生理学中间表型数据集：247 个美国白种人、365 个酗酒患病率较高的平原美洲印第安人以及 198 个酗酒患病率较低的东南美洲印第安人。我们还与密歇根大学的 Zubietta 博士和 NIDA 的 Stein 博士合作，研究成像数据（功能磁共振成像和正电子发射断层扫描 (PET)）作为成瘾相关表型的中间表型。 对平原印第安人样本的全基因组连锁扫描没有发现酗酒的连锁信号。然而，5 号染色体 (chr) 上的 α、β 和 θ EEG 功率连锁峰收敛，LOD 得分为 3.5。促肾上腺皮质激素释放激素结合蛋白（CRHBP）的基因位于会聚连锁峰的顶点。 CRHBP 与压力和成瘾有关。随后的分析表明，CRHBP SNP 和单倍型与平原印第安人和美国白种人的 α 脑电图功率显着相关。此外，相同的 CRHBP SNP 与平原印第安人的焦虑症和美国白种人的酒精使用障碍显着相关（Enoch 等，2008）。这些结果表明 CRHBP 在包括酗酒在内的压力相关疾病中可能发挥作用。事实上，我们最近表明，在具有物质依赖的非洲裔美国男性样本中，相同的远端 CRHBP SNP 可以预测那些曾遭受过严重童年创伤的个体的自杀行为（Roy 等，2012）。 CRHBP 通过几个单倍型块与相邻基因缓冲，表明功能基因座可能位于该基因或其周围区域。我们已经证明大脑中存在另一种 CRHBP 亚型，其中末端外显子被剪接成两个替代外显子，导致肽序列发生变化，可能影响蛋白质折叠和稳定性，从而导致 CRH 结合亲和力改变。目前正在进行功能研究。 在第 22 条上发现了 LOD 得分为 3.2 的 θ EEG 功率连锁峰。在第 4、10 和 11 条上有提示性峰值（LOD = 2.2 至 2.5）。在第 11 条连锁峰的顶点有三个候选基因：血清素受体 3A 和 3B（HTR3A 和 HTR3B）以及 DRD2。我们发现平原印第安人和美国白种人的 HTR3B 与脑电图 α 功率之间存在显着关联，而芬兰白种人的 HTR3B 与反社会酗酒之间存在显着关联（Ducci 等，2009）。此外，在药物滥用的非裔美国男性样本中，我们发现功能性 HTR3B SNP rs1176744 与酒精依赖相关（Enoch 等，2011）。我们的研究表明，中间表型对于识别酒精中毒高发人群中的基因特别有用。 最近与 Zubietta 博士的合作研究表明，仅在女性中，催产素基因的遗传变异与压力诱导的多巴胺激活（通过 PET 测量）有关，多巴胺激活是酗酒的脆弱因素（Love 等，2012）。此外，编码压力反应 CRH1 受体的 CRHR1 基因的变异与对情绪刺激的神经反应（通过功能磁共振成像测量）的差异相关（Hsu 等人，2012），这可能表明容易受到压力相关疾病（包括酗酒）的影响。最后，在与 NIDA 的 Stein 博士小组的合作中，我们发现尼古丁和 COMT Val158Met 基因型在奖励处理过程中调节皮质纹状体网络的激活（通过 fMRI 测量）（Lee 等人提交）。 以前的标题是“脑电图和事件相关电位的遗传学研究”和“与酗酒相关的脑电图和 ERP 特征的遗传学研究”。