JOEL E GELERNTER

..003). These findings replicate and extend recently reported findings, which together underscore the potential contribution of polymorphic variation at the GABRA2 locus to the risk for alcohol dependence...

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..Functional studies of these loci are warranted. These results provide additional information useful in evaluating the many earlier discrepant findings regarding association of DRD2 with substance dependence...

..Nicotine dependence (ND) is costly to societies worldwide, moderately heritable, and genetically complex. Risk loci can be identified with genetic linkage analysis independent of prior physiological hypotheses...

..Interestingly, one of our most promising linkage regions, includes a region previously identified as linked to PD...

..These results are an initial step in identifying genes for opioid dependence on the basis of a genomewide investigation (i.e., a study not conditioned on prior physiological candidate-gene hypotheses)...

..We found significant differences in allele frequency between populations, and a maximum frequency of the 80G allele of 9%, in each of two European populations. This variant could contribute to the previously reported association results...

..We propose that the intronic VNTR have been selectively targeted through mammalian evolution to finetune transcriptional regulation of the serotonin expression...

..Although considerable progress has been made, it is likely that the application of more extensive sequencing than has previously been practical will be required to identify a fuller range of risk variants...

..35 for membership in the "Moderate Cocaine and Opioid Abuse" cluster on chromosome 18. These results provide a basis for the identification of specific genes contributing to risk for these traits...

..A previous report suggested that a functional variant at the genetic locus encoding the mu opioid receptor (Asn40Asp) is such a marker, in short-term (3-month) treatment with the opioid-blocking drug naltrexone (NTX)...

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..Genetic linkage analysis can provide the means to identify genomic locations harboring susceptibility loci for genetically influenced disorders. Identifying loci for social phobia was the goal of this study...

..Overall, the results presented here suggest that PD and agoraphobia are complex traits that share some, but not all, of their susceptibility loci. Published 2001 Wiley-Liss, Inc...

..These findings suggest that OPRM1 may play a role in the pathophysiology of substance dependence and this role is population- and diagnosis-specific...

..Risk loci in several populations have been identified with genetic linkage analysis. To date, there has been no published linkage study of AD focused on African Americans (AAs)...

..abstract:..

..This is the first genome scan linkage study for simple phobia, a common disorder that causes high morbidity in the US population...

..Because the convergence of these disorders may provide a refined phenotype, we examined the association of serotonin (5-HT) transporter linked polymorphic region (5-HTTLPR) alleles to comorbid alcohol dependence and major depression...

..019). We conclude that two independent CNR1 variants have significant interaction effects on risk for CD in EAs; they may also have effects on risk for CD in AAs...

..SNP2 or SNP6 was the marker genetically closest to the functional risk loci for both alcohol dependence and drug dependence...

..Using rigorous study designs that account for possible population stratification, these findings confirm and extend our original observations indicating that variation at ADH4 predisposes to alcohol and drug dependence...

..The complexity of these relationships, many of which replicate between our independent samples, may explain prior inconsistent results...

..Previous studies generally focused on its effect on depressive symptoms; little is known about its moderation of the development of posttraumatic stress disorder (PTSD)...

..The negative results for AFDs, PTSD, and schizophrenia could be due to the low statistical power. Further study with larger samples is warranted...

..Other functional variants may exist that contribute to this relationship. Possible sex-specific effects remain to be further studied and explained...

..We tested whether the Pro7 allele is associated with alcohol dependence in European Americans (EA)...

..Following initial reports of association of CNR1 with SD, we studied multiple markers at this locus in a large case-control sample...

..Because comorbid AD with DD (AD+DD) is common, we hypothesized that heterogeneity of the SD diagnoses studied might have contributed to the inconsistency of prior results...

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..These findings fail to replicate the original report of an association between SNPs adjacent to an alternative CNR1 exon 3 transcription start site and polysubstance abuse...

..These results provide a direct example of the potential value of constructing a haplotype map of the human genome prior to embarking on large-scale association studies...

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..The goal of this study was to investigate the relationship between the NOTCH4 gene and schizophrenia in African American (AA) and European American (EA) subjects...

..The present study examines the association of a GABRA2 SNP with another definition of alcohol involvement and with the effects of psychosocial treatment...

..The pro-opiomelanocortin gene (POMC) encodes several peptides important for endogenous opioidergic neurotransmission. We tested whether POMC genetic variation affects risk for substance dependence...

..008 <or= P <or= 0.060). The present study demonstrates that the ADH1A variation may contribute to the genetic component of variation in personality traits and SD...

..These findings, obtained using a series of powerful and reliable analytic methods, may also help to explain the high rate of co-morbidity between AD and DD...

..Conclusion: Despite no evidence in this study for allelic association of HTR1B to antisocial substance dependence, further evaluation of the hypothesized association is warranted in other population groups...

..This study provides further evidence of a gene x environment effect of FKBP5 and childhood abuse on the risk for PTSD in AAs. Further study is required in other populations...

..These findings may aid in understanding the genetic association of this locus with alcohol dependence in several populations...

..If replicated, these results would help to identify alcohol-dependent individuals who may be most likely to respond to treatment with naltrexone...

..In addition, a specific diplotype might inversely affect risk for AD and DD and risk for affective disorders...

..We conclude that variation in KIBRA influences cognitive flexibility in a population-specific way, and that current smoking status moderates this effect...

..These findings suggest that OPRM1 intronic variants play a role in susceptibility to AD and DD in populations of European ancestry...

..This work suggests that variations in the TPH2 gene are not a risk factor for the development of cocaine dependence, but these findings require confirmation in larger, independent samples of cocaine-dependent and control subjects...

..We also found that several ADH genes and the ALDH2 gene were susceptibility loci for AD, and the associations were best explained by several independent risk genes...

..We examined the possibility that allelic variation leading to alterations in beta(1)-adrenergic function might be present in persons with elevated social anxiety-related traits...

..The number of markers required is much lower than has been suggested in previous studies...

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..CONCLUSIONS: Severity of cocaine dependence and age of onset appear to be important risk factors for CIP. Concordance for CIP between siblings did not emerge as significant in our analyses...

..The effect of the Val66Met polymorphism on premorbid educational attainment is intriguing and should be verified in a larger sample...

..Variation in the gene for dopamine beta-hydroxylase (DbetaH) has been reported to associate with cocaine-induced paranoia as assessed by retrospective self-report. This association has yet to be tested prospectively...

..This direct method of comparison seemed to demonstrate the superior validity of the multivariate cluster-analytic approach over the univariate approaches to classifying subjects with drug dependence...

..Furthermore, these findings begin to establish a haplotype map for this gene in the AA and EA populations...

..The identification of genetic factors controlling stress-responsiveness should advance the understanding of susceptibility to psychiatric illness...

..Comorbid substance use and psychiatric disorders are very common among individuals with cocaine dependence. Comorbid ADHD increases the odds of an individual endorsing CIP, suggesting some common basis for these phenomena...

..Numerous putative susceptibility loci have been identified, but only a few of these were replicated in independent studies...

..We cannot exclude the possibility that the results might have been influenced by selection bias due to the multisite nature of the study...

..Further, the three OPR genes have significant interaction effects on personality traits. This work provides additional evidence that personality traits and SD have a partially overlapping genetic basis...

..Child abuse and genotype interact to contribute to risk for depression in children. This study examined gene-by-gene and gene-by-environment interactions...

..Here we sought to determine the functional relevance of this variation...

..Advances in molecular neuroscience, genetics, and neuroimaging provide new insights into the role of brain GABA systems in short- and long-term alcohol effects...

..In vitro studies of nonneural cells have suggested that the long allele may have higher transcriptional activity than the short allele. However, the relevance of these findings for SERT levels in the brain remains unclear...

..The functional promoter GAD2 -243 A > G variant may influence risk for AD in some populations, or its role may be limited to susceptibility to severe AD...

..Strong associations between ADH4 variation and SD have been reported. We aimed to investigate the relationship between ADH4 variation and personality traits in the present study...

..These findings suggest that common genetic mechanisms influence certain biochemical and behavioral aspects of stimulant responsiveness...

..The high concordance between instruments supports the concurrent validity of the diagnosis. Either interview provides reliable, valid OD diagnoses in Thai-speaking Hmong individuals...

..These results suggest that the minor G-allele of SNP rs569356 may enhance transcription factor binding and increase OPRD1 expression...

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..The goal of this study was to test whether GABRA2 is associated with alcohol dependence in a sample of Russian alcohol-dependent men...

..Previous investigations of the effects of the SLC6A3 polymorphism on DAT availability in smaller samples of humans have yielded divergent results...

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..Furthermore, these results suggest that common genetic variation within the GAD67 gene does not play a major role in the predisposition to unipolar depression...

..These results do not support the involvement of genetic variation in these three circadian gene SNPs for influencing risks for either of these cocaine phenotypes...

..The goal of the current investigation was to examine genetic and environmental predictors of early alcohol use, a potent predictor of later alcohol dependence...

..Although the heritability of nicotine dependence (ND) is well documented and many candidate genetic regions have been identified, few of them were confirmed. This may be, in part, due to analytic methods that sacrifice power...

..002). CHRM2 variation may contribute to the genetic component of variation in personality traits. Personality traits might substantially underlie the heritable component of SD...

..The present study demonstrated that the ADH7 variation may contribute to the genetic component of variation in personality traits, with the risk for SD and personality traits being partially shared...

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..Successful completion of this research would be expected to increase our understanding of alcohol dependence, and potentially to lead to early identification of susceptible individuals, and to new treatments. ..

..The project will also contribute to a substantial increase in our understanding of the mechanisms of CD, and may lead to new approaches to the prevention and treatment of this pervasive societal problem. ..

..The conduct of these studies will provide excellent opportunities for research training. This proposal would permit the PI to make a major investment in mentorship, and allow a broadening of his research program in substance dependence. ..

..Given that CD is a complex trait, a large ASP study that will allow genetic analysis without assumptions about trait transmission will provide the best chance to map genes related to this dangerous, prevalent disorder. ..

..Collection of a sample such as the one proposed here is a necessary step towards identifying specific genes that predispose for AD. Loci identified will be expected to have particular relevance for the AA community. ..

..This study will improve understanding of the genes that influence risk for alcohol dependence, in Chinese populations, and in comparison with European-American populations. ..

..The project will also contribute to a substantial increase in our understanding of the mechanisms of CD, and may lead to new approaches to the prevention and treatment of this pervasive societal problem. ..

..Successful completion of this research would be expected to increase our understanding of alcohol dependence, and potentially to lead to early identification of susceptible individuals, and to new treatments. ..

..Successful completion of this research would be expected to increase our understanding of alcohol dependence, and potentially to lead to early identification of susceptible individuals, and to new treatments. ..

..Successful completion of this research would be expected to increase our understanding of alcohol dependence, and potentially to lead to early identification of susceptible individuals, and to new treatments. ..

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..For example, the DRD4*7R allele has been reported by two groups to associate to novelty-seeking personality. We propose to evaluate this relationship in a sample of alcoholic subjects. This work all builds on the HRR sample. ..

..This program of research will improve our understanding of the genetics underlying human brain responses to chronic cocaine exposure, thus leading to better diagnosis and treatments for cocaine dependence and other addictive disorders. ..