From QTL to Candidate Gene: A Genetic Approach to Alcoholism Research

Abstract

A major focus of research in alcohol-related disorders is to identify the genes and pathways that modulate alcohol-seeking behavior. In light of this, animal models have been established to study various aspects of alcohol dependence. The selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines were developed from Wistar rats to model high and low voluntary alcohol consumption, respectively. Using inbred P and NP strains, a strong QTL (LOD-9.2) for alcohol consumption was identified on rat chromosome 4. To search for candidate genes that underlie this chromosomal region, complementary molecular-based strategies were implemented to identify genetic targets that likely contribute to the linkage signal. In an attempt to validate these genetic targets, corroborative studies have been utilized including pharmacological studies, knock-out/transgenic models as well as human association studies. Thus far, three candidate genes, neuropeptide Y (Npy), α-synuclein (Snca), and corticotrophin-releasing factor receptor 2 (Crhr2), have been identified that may account for the linkage signal. With the recent advancements in bioinformatics and molecular biology, QTL analysis combined with molecular-based strategies provides a systematic approach to identify candidate genes that contribute to various aspects of addictive behavior.

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

“…Future research should use next-generation DNA sequencing to identify genomic signatures of selection between P and NP rats and next-generation RNA sequencing methodologies to analyze allele-specific expression of genes in F1 crosses of these lines (e.g., Farris & Mayfield, 2014; Wang, Kapoor, & Goate, 2012). This will help move the field from QTL analyses to quantitative trait nucleotide [QTN; i.e., (SNPs)] and quantitative trait gene (QTG) analyses (e.g., Ehlers, Walter, Dick, Buck, & Crabbe, 2010; Milner & Buck, 2010; Spence et al, 2009). By doing so, the level of genomic resolution and the power of these analyses will be exponentially increased over the existing techniques.…”

Effects of histone deacetylase inhibitors on amygdaloid histone acetylation and neuropeptide Y expression: a role in anxiety-like and alcohol-drinking behaviours

“…For several years, NPY in the amygdala has been implicated in the mechanisms of anxiety disorders and alcoholism, using various animal models and treatment paradigms (Pandey 2003; Thiele and Badia-Elder, 2003; Heilig 2004; Spence et al, 2009). The deficits in NPY levels in the amygdala of P rats as compared to NP rats have been reported (Hwang et al, 1999; 2004a; Suzuki et al, 2004).…”

Quantitative Proteomics in Laser Capture Microdissected Sleep Nuclei From Rat Brain

“…The functions of SNCA continue to emerge, and the question remains as to why CNP remains active during induced sleep whereas MBP appears to be decreased by the ORA treatment. The change in SNCA levels in response to Ox-B in the VTA is intriguing given the recent linkage of this gene with addictive behaviors in rodents (Spence et al, 2009) and humans (Clarimon et al, 2007; Bonsch et al, 2005). Although many of the peptides identified have been linked with CNS function and some pathologies, the relevance of the observed changes in VTA in response to peptide or antagonist treatment remains to be determined.…”