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

基本信息

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
项目类别：
财政年份：
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

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

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项目摘要

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".

然而，在男性和女性中，酒精中毒的遗传力均为40-60％，但是在其他复杂的精神病中，事实证明，很难识别病因基因。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，并且可能介导该疾病的不同方面。我们正在研究的酒精中毒的中间表型包括维度焦虑（避免伤害），静止的EEG表型和与事件相关的电位（ERP）。我们有三个大型的电生理中间表型数据集：247个美国高加索人，365个平原的美国印第安人，酗酒率很高，198个东南美洲印第安人的酒精中毒患病率低。与密歇根大学的Zubietta博士和NIDA的Stein博士合作，我们还研究了成像数据（fMRI和正电子发射断层扫描（PET）），作为成瘾相关表型的中间表型。在平原印度样本中进行的整个基因组连锁扫描没有识别出酒精中毒的连锁信号。但是，染色体（CHR）5上的Alpha，beta和Theta EEG功率的连锁峰值有3.5的LOD分数。皮质激素释放激素结合蛋白（CRHBP）的基因位于收敛链接峰的顶点。 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高加索人的αEEG功率显着相关。此外，同一CRHBP SNP与印第安人和酒精使用障碍的焦虑症显着相关（Enoch等，2008）。这些结果表明，CRHBP在包括酒精中毒在内的与压力有关的疾病中可能起作用。确实，我们最近表明，在具有物质依赖性的非裔美国人男性中，同一远端CRHBP SNP预测了那些受到严重童年创伤的人的自杀行为（Roy等，2012）。 CRHBP通过几个单倍型块从相邻基因中缓冲，表明功能基因座可能位于该基因或其周围环境中。我们已经证明了在大脑中存在替代性CRHBP同工型，其中将末端外显子剪接而有利于两个替代外显子，从而导致肽序列的变化，从而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。功能研究目前正在进行中。在CHR 22上发现了Theta EEG功率的连锁峰为3.2。在CHRS 4、10和11上有暗示性峰（LOD = 2.2至2.5）。在CHR 11：5-链接峰的顶点上有三个候选基因：5-羟色胺受体3A和3B和3B（HTR3A和HTR3B和HTR3B）和DRD2。我们发现印第安人和美国高加索人的HTR3B和EEG Alpha能力之间存在显着关联，以及芬兰高加索人的反社会酒精中毒（Ducci等，2009）。此外，在非裔美国人滥用药物的样本中，我们发现功能性HTR3B SNP RS1176744与酒精依赖有关（Enoch等，2011）。我们的研究表明，中间表型对于鉴定该疾病高患病率的酗酒基因特别有用。最近与Zubietta博士进行的合作研究表明，仅在女性中，催产素基因的遗传变异与应激诱导的多巴胺激活（通过PET测量）有关，这是酒精中毒的脆弱性因素（Love等，2012）。同样，编码应力 - 响应CRH1受体的CRHR1基因的变化与神经反应（通过fMRI测量）对情绪刺激的差异（Hsu等，2012）可能表明可能表明与包括酒精中毒在内的压力相关疾病的脆弱性。最后，在与NIDA的Stein's Group的合作中，我们表明尼古丁和COMT Val158MET基因型调节在奖励处理过程中在皮质层网络中调节激活（通过fMRI测量）（Lee等人，已提交）。以前的标题为“脑电图和事件相关电位的遗传研究”和“与酒精中毒有关的脑电图和ERP特征的遗传研究”。