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: 7591932
• 负责人: David Goldman
• 金额: $ 27.56万
• 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/7591932
• 关键词: Alcoholism; American Indians; Anxiety; Anxiety Disorders; Biological; Candidate Disease Gene; Caucasians; Caucasoid Race; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 5; Complex; DRD2 gene; Data Set; Disease; Electroencephalogram; Electroencephalography; Event-Related Potentials; Frequencies; Future; Genes; Genetic; Genome; HTR3A gene; Heart Rate; Heritability; High Prevalence; Individual; Lod Score; Low Prevalence; Mediating; Mental disorders; Phenotype; Population; Rest; Sampling; Scanning; Stress; Time; Variant; Woman; addiction; anti social; corticotropin releasing factor-binding protein; genetic linkage analysis; genetic pedigree; men; problem drinker; serotonin receptor; 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 (HA)), resting EEG phenotypes, event-related potentials (ERPs) and heart rate variability (HRV). We have three large 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. We have recently performed a dense whole genome linkage scan with 3878 unlinked SNPs spaced at an average distance of 1cM on the Plains Indian sample. These Plains Indians derive from six pedigrees, the largest of which includes 1004 individuals. Linkage analysis was performed using SOLAR. There was no significant linkage with alcoholism in the Plains Indians. We then looked for linkage with resting EEG power, an intermediate phenotype for alcoholism. We found that EEG power was stable over time and moderately heritable across all frequency bands (0.30 0.60). 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 corticotrophin releasing hormone binding protein (CRH-BP) was located at the apex of the linkage peaks. CRH-BP is implicated in stress and addiction. Subsequent analyses showed that CRH-BP was significantly associated with alpha EEG power in the Plains Indians and also the U.S. Caucasians. (Enoch et al., submitted). In addition, CRH-BP was significantly associated with anxiety disorders and HA in the Plains Indians, alcoholism in the U.S. Caucasians, and HA in a group of Finnish alcoholics. 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 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., submitted). We will be looking at other candidate genes under the linkage peaks in the near future. Our studies have shown that intermediate phenotypes are particularly useful for identifying genes for alcoholism in populations with a high prevalence of this disease. 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（避免危害（HA）），静止的脑电图表型，与事件相关电位（ERP）和心率变异性（HRV）。我们有三个大型中间表型数据集：247个美国高加索人，365个平原，美国印第安人的酒精中毒患病率很高，198个美国印第安人的酗酒率低。 最近，我们进行了密集的整个基因组链接扫描，在平原印度样本上，平均距离为1厘米的3878未链接SNP。这些平原印第安人衍生出六个血统，其中最大的是1004个人。使用太阳能进行链接分析。在印第安人平原上，与酒精中毒没有显着联系。然后，我们寻求与静息脑电的链接，静息电力是酒精中毒的中间表型。 我们发现，随着时间的流逝，EEG功率在所有频段（0.30 0.60）中稳定。染色体（CHR）5上的Alpha，beta和Theta EEG功率的连锁峰融合，LOD得分为3.5。皮质营养素释放激素结合蛋白（CRH-BP）的基因位于连锁峰的顶点。 CRH-BP与压力和成瘾有关。随后的分析表明，CRH-BP与平原印第安人和美国高加索人的Alpha EEG功率显着相关。 （Enoch等人，提交）。 此外，CRH-BP与印第安人平原上的焦虑症和HA显着相关，美国高加索人的酒精中毒以及一组芬兰酒精中毒的HA。 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 2.5）。在ChR 11：5-羟色胺受体3A和3B和3B（HTR3A和HTR3B）和HTR3B和DRD2的链接峰的顶点上有三个候选基因。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等人，提交）。 在不久的将来，我们将在连锁峰下查看其他候选基因。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。 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”。