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".

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（HA））、静息脑电图表型、事件相关电位（ERP）和心率变异性（HRV）。我们拥有三个大型中间表型数据集：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。 我们最近对平原印第安人样本进行了密集的全基因组连锁扫描，其中有 3878 个未连锁的 SNP，平均距离为 1cM。这些平原印第安人有 6 个血统，其中最大的血统有 1004 人。使用 SOLAR 进行连锁分析。与平原印第安人酗酒没有显着联系。然后我们寻找与静息脑电图功率的联系，这是酒精中毒的中间表型。 我们发现脑电图功率随着时间的推移保持稳定，并且在所有频段上具有适度的遗传性（0.30 0.60）。 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（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白种人的 α 脑电图功率显着相关。 （Enoch 等人提交）。 此外，CRH-BP 与平原印第安人的焦虑症和 HA、美国白种人的酗酒以及芬兰酗酒者的 HA 显着相关。 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 条上有暗示性峰值 (LOD = 2.2 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 等人提交）。 我们将在不久的将来研究连锁峰下的其他候选基因。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。 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”。