A method for mapping intralocus interactions influencing excessive alcohol drinking

Abstract

Excessive alcohol (ethanol) consumption is the hallmark of alcohol use disorders. The F1 hybrid cross between the C57BL/6J (B6) and FVB/NJ (FVB) inbred mouse strains, consumes more ethanol than either progenitor strain. The purpose of this study was to utilize ethanol drinking data and genetic information to map genes that result in over-dominant (or heterotic) ethanol drinking. About 600 B6 × FVB F2 mice, half of each sex, were tested for ethanol intake and preference in a 24-h, two-bottle water versus ethanol choice procedure, with ascending ethanol concentrations. They were then tested for ethanol intake in a drinking in the dark (DID) procedure, first, when there was no water choice and then when ethanol was offered versus water. DNA samples were obtained and genome-wide QTL analyses were performed to search for single QTLs (both additive and dominance effects) and interactions between pairs of QTLs, or epistasis. On average, F2 mice consumed excessive amounts of ethanol in the 24-h choice procedure, consistent with high levels of consumption seen in the F1 cross. Consumption in the DID procedure was similar or higher than amounts reported previously for the B6 progenitor. QTLs resulting in heightened consumption in heterozygous compared to homozygous animals were found on Chr 11, 15 and 16 for 24-h choice 30% ethanol consumption, and on Chr 11 for DID. No evidence was found for epistasis between any pair of significant or suggestive QTLs. This indicates that the hybrid over-dominance is due to intralocus interactions at the level of individual QTL. KeywordsHeterosis; addiction; gene mapping; epistasis; alcoholism Excessive alcohol (ethanol; EtOH) use disorders appear to have multiple etiologies. For example, they may develop as a consequence of poor impulse control Crews and Boettiger, 2009), genetic risk (Bohman et al. 1987;Schuckit 2009), or the interaction of heritable factors with environmental factors, such as parental divorce (Thompson et al. 2008). Behavioral and expression quantitative trait locus (QTL) mapping studies in rodents and humans have identified chromosomal regions, and nominated candidate genes, that may influence EtOH drinking (Belknap and Atkins 2001;Mulligan et al. 2006;Tabakoff et al. 2008;Ducci and Goldman, 2008). The majority of studies have focused on providing evidence for the locations of genes that independently influence EtOH intake; in combination, these genes account for a larger proportion of variation in intake than does each gene when considered alone. Technological advances are leading to more sophisticated gene network analyses designed to identify important signaling pathways (e.g., Song et al. 2009 (Godoy-Herrera, 1994;Chesler et al. 2005), including EtOH-related traits (Bergeson et al. 2003;Hood et al. 2001;Kuo et al. 2008;Palmer et al. 2003), and there is a need for the further development of methods for identifying these genetic interactions.Mice from the first filial (F1) cross of the C57BL/6J (B6) and FVB/NJ (FVB) inbred mouse strains have been documented...

High Drinking in the Dark Mice: A genetic model of drinking to intoxication

“…HS/Npt mice have not been used as the starting population for any other alcohol-selected lines, and consequently QTL results may differ in part because the alleles available during HDID selection are different from those found in the other inbred strain crosses used for mapping. This possibility is supported by the fact that potential QTLs identified here also failed to overlap with possible QTLs for DID identified previously using a B6 × FVB/NJ F2 population (Phillips et al, 2010). However, mice in that study were tested for DID after more than 3 weeks of daily, 2-bottle choice drinking whereas Iancu and colleagues used naïve HDID and HS mice for their QTL mapping experiment.…”

Epigenetics and Biomarkers in the Staging of Neuropsychiatric Disorders

“…In addition, this study confirms the regulatory role of brain derived neurotrophic factor (BDNF) upon mesolimbic dopaminergic pathways (Bahi et al 2008;Van Winkel et al 2008;Post 2010). Genetic epistasis ought to provide an important role in the etiopathogenesis of neuropsychiatric disorders, including alcohol addiction (Wu and Shete 2005;Phillips et al 2010) and schizophrenia, where epistasis between DISC1, CIT, and NDEL1 impacting risk for schizophrenia has been validated biologically through functional neuroimaging using fMRI (Nicodemus et al 2010).…”

Distinct ethanol drinking microstructures in two replicate lines of mice selected for drinking to intoxication

“…This likely reflects the attenuated HDID phenotype that is seen here and in previous studies during two-bottle choice DID wherein ethanol intake and BEC are lower than that seen with single-bottle DID (Barkley-Levenson & Crabbe, 2012; Crabbe et al, 2012). Continuous access two-bottle choice preference drinking and DID have been shown to be largely genetically distinct traits (Phillips et al, 2010; Crabbe et al, 2012), but it is not yet clear what the genetic relationship may be between intake in a two-bottle choice DID and a single-bottle DID test. However, the present results suggest that the bout structure of ethanol intake does seem to generalize across procedures.…”

“…Ethanol intake during DID and the more commonly used 24 hr, two-bottle choice preference drinking procedures undoubtedly have shared genetic components, but there is evidence that these traits have distinct genetic contributions as well. Specifically, quantitative trait locus (QTL) mapping efforts have identified only minimal chromosomal overlap between QTLs implicated in continuous access two-bottle choice drinking and DID (Iancu et al, 2013; Phillips et al, 2010). HDID mice represent a novel genetic model of risk for binge-like drinking.…”