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"""""""".
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