Intermediate Phenotypes for Alcoholism and Whole Genome Linkage Scan

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，很难确定致病基因。中间表型是相关的生物学性状，可能受到较少基因变异的影响，并可能介导疾病的不同方面。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）、静息脑电图表型和事件相关电位（ERPs）。我们有三个大型的电生理中间表型数据集：247名美国白种人，365名酗酒高发的美洲平原印第安人和198名酗酒低发的美洲东南部印第安人。与密歇根大学的Zubietta博士和NIDA的Stein博士合作，我们也在研究成像数据（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。

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".