Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach

Abstract

We describe a comprehensive translational approach for identifying candidate genes for alcoholism. The approach relies on the cross-matching of animal model brain gene expression data with human genetic linkage data, as well as human tissue data and biological roles data, an approach termed convergent functional genomics. An analysis of three animal model paradigms, based on inbred alcohol-preferring (iP) and alcohol-non-preferring (iNP) rats, and their response to treatments with alcohol, was used. A comprehensive analysis of microarray gene expression data from five key brain regions (frontal cortex, amygdala, caudate-putamen, nucleus accumbens and hippocampus) was carried out. The Bayesian-like integration of multiple independent lines of evidence, each by itself lacking sufficient discriminatory power, led to the identification of high probability candidate genes, pathways and mechanisms for alcoholism. These data reveal that alcohol has pleiotropic effects on multiple systems, which may explain the diverse neuropsychiatric and medical pathology in alcoholism. Some of the pathways identified suggest avenues for pharmacotherapy of alcoholism with existing agents, such as angiotensin-converting enzyme (ACE) inhibitors. Experiments we carried out in alcohol-preferring rats with an ACE inhibitor show a marked modulation of alcohol intake. Other pathways are new potential targets for drug development. The emergent overall picture is that physical and physiological robustness may permit alcohol-preferring individuals to withstand the aversive effects of alcohol. In conjunction with a higher reactivity to its rewarding effects, they may able to ingest enough of this nonspecific drug for a strong hedonic and addictive effect to occur.

Targeting brain angiotensin and corticotrophin-releasing hormone systems interaction for the treatment of mood and alcohol use disorders

“…The regional specificity is interesting and in line with the microarray studies in high-preferring rats [18,19]. Inhibition of AngII production by 5 mg/kg spirapril, an ACE inhibitor that efficiently crosses the blood brain barrier and that according to experiments in Agt knockout mice reduces ethanol consumption via central Ang II action [16], was more potent in reducing ethanol intake in postdependent rats compared to controls [28].…”

“…Recent studies in animals with genetic modification in various components of the RAS demonstrate that Ang II via AT 1 action is a positive modulator of spontaneous ethanol consumption in rodents [15,16]. Furthermore, increased expression of Agt was found in microarray studies of brains from different rodent lines selectively bred for high ethanol preference (HAP mice, P and AA rats) compared to their respective controls [17][18][19]. Bioinformatic analysis of known genegene interactions among differential expressed genes in these animals identified Agt as a key node in the interaction network.…”

“…Bioinformatic analysis of known genegene interactions among differential expressed genes in these animals identified Agt as a key node in the interaction network. Functional validation for the increased Agt expression is provided by the demonstration that lisinopril or ceranapril, two inhibitors of angiotensinconverting enzyme (ACE), reduce voluntary ethanol consumption in P rats [18,20].…”

Functional gene expression differences between inbred alcohol-preferring and –non-preferring rats in five brain regions

“…In one study, the present HIPP data were used with other HIPP data to evaluate the reliability of the microarray analysis, when assays were conducted months apart (Edenberg et al, 2005). In the second study (Rodd et al, 2006), the data were used as part of a convergent functional genomics approach to identify common genes across different experimental approaches and between human and animal findings. In that study, however, the iP-iNP data were not analyzed using rigorous statistical criteria (for a gene to be considered significant, an false discovery rate (FDR)-uncorrected P <.05 was considered sufficient), and the results were presented only in a summarized format, which were then integrated with information from other studies.…”

Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

“…The application of comprehensive, integrative approaches will define the future of alcohol research (Rodd et al, 2007;Tabakoff et al, 2009;Tapocik et al, 2013) and promises to be fruitful in elucidating the mechanisms underlying alcohol addiction. Genetic and biological studies in animal models or post-mortem human brain, with epidemiological and clinical surveys on human subjects, should be integrated with genomic data.…”