Intermediate Phenotypes for Alcoholism and Whole Genome Linkage Scan

然而，酒精中毒在男性和女性中的遗传率都是40%-60%，而在其他复杂的精神疾病中，事实证明很难确定致病基因。中间表型是相关的生物性状，可能受到较少基因变异的影响，并可能调节疾病的不同方面。我们正在研究的酒精中毒的中间表型包括维度焦虑(伤害避免(HA))、静息脑电表型、事件相关电位(ERPs)和心率变异性(HRV)。我们有三个大型的中间表型数据集：247名美国高加索人，365名酗酒高发的平原美洲印第安人和198名酗酒低患病率的美国东南部印第安人。 我们最近进行了密集的全基因组连锁扫描，在Plains印度样本上，3878个未连锁的SNP平均间距为1 cM。这些平原印第安人来自六个家系，其中最大的包括1004个个体。利用SOLAR软件进行连锁分析。在平原印第安人中，这与酗酒没有明显的联系。然后，我们寻找与静息脑电功率的联系，这是酒精中毒的一种中间表型。 我们发现，脑电功率随着时间的推移是稳定的，并且在所有频段(0.27到0.58)上都具有适度的遗传性。α、β和theta脑电在染色体上的功率(CHR)5的连锁峰集中，LOD评分为3.5。促肾上腺皮质激素释放激素结合蛋白(CRH-BP)基因位于聚合连锁峰的顶端。CRH-BP与压力和成瘾有关。随后的分析表明，在平原印第安人和美国高加索人中，CRH-BP与阿尔法脑电功率显著相关。此外，CRH-BP与平原印第安人的焦虑症和美国高加索人的酒精使用障碍显著相关(Enoch等人，2008年)。CRH-BP通过几个单倍型块与相邻基因缓冲，表明一个功能位点可能位于该基因或其周围。我们已经证明了在大脑中存在一种替代的CRH-BP亚型，在这种亚型中，末端外显子被剪接出来，导致两个替代的外显子，导致多肽序列的变化，这可能会影响蛋白质的折叠和稳定性，从而改变CRH结合亲和力。我们的结果表明CRH-BP在应激相关的酒精中毒中可能起到作用，并强调了静息脑电作为焦虑和成瘾等唤醒相关行为的中间表型的使用。 在CHR 22上发现了一个连锁峰值，其LOD分数为3.2。在CHR4、10和11上均有提示峰(LOD=2.2~2.5)。在CHR11的连锁峰顶有3个候选基因：5-羟色胺受体3A和3B(HTR3A和HTR3B)和DRD2。我们发现，在平原印第安人和美国高加索人中，HTR3B和EEGα功率之间存在显著关联，而在芬兰高加索人中，HTR3B与反社会酒精中毒之间存在显著关联(Ducci等人，2009年)。此外，在一个有药物滥用的非裔美国人男性样本中，我们发现HTR3B单倍型和一个功能性SNP rs1176744与酒精依赖有关(Enoch等人提交)。 我们将在不久的将来寻找连锁高峰下的其他候选基因。我们的研究表明，中间表型对于在这种疾病高发人群中识别酒精中毒的基因特别有用。 以前的标题是“脑电和事件相关电位的遗传研究”和“与酒精中毒有关的脑电和事件相关电位特征的遗传研究”。

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 (0.27 to 0.58). 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 convergent 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. Moreover, CRH-BP was significantly associated with anxiety disorders in the Plains Indians and alcohol use disorders in the U.S. Caucasians (Enoch et al., 2008). CRH-BP 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 CRH-BP 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. Our results suggest a likely role for CRH-BP in stress-related alcoholism and highlight the use of the resting EEG as an intermediate phenotype for arousal-related behaviors such as anxiety and addiction. 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.,2009). Moreover, in a sample of African American men with substance abuse, we found that HTR3B haplotypes and a functional SNP rs1176744 were associated with alcohol dependence (Enoch 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".