Genetic Contribution to Initial and Progressive Alcohol Intake Among Recombinant Inbred Strains of Mice.

Megan K Mulligan,Wenyuan Zhao,Lu Lu,Danny Arends,Pjotr Prins,Elena Terenina,Morgan Dickerson,Sonia A Cavigelli,Pierre Mormede,Byron C Jones

doi:10.3389/fgene.2018.00370

Abstract

We profiled individual differences in alcohol consumption upon initial exposure and during 5 weeks of voluntary alcohol intake in female mice from 39 BXD recombinant inbred strains and parents using the drinking in the dark (DID) method. In this paradigm, a single bottle of 20% (v/v) alcohol was presented as the sole liquid source for 2 or 4 h starting 3 h into the dark cycle. For 3 consecutive days mice had access to alcohol for 2 h followed by a 4th day of 4 h access and 3 intervening days where alcohol was not offered. We followed this regime for 5 weeks. For most strains, 2 or 4 h alcohol intake increased over the 5-week period, with some strains demonstrating greatly increased intake. There was considerable and heritable genetic variation in alcohol consumption upon initial early and sustained weekly exposure. Two different mapping algorithms were used to identify QTLs associated with alcohol intake and only QTLs detected by both methods were considered further. Multiple suggestive QTLs for alcohol intake on chromosomes (Chrs) 2, 6, and 12 were identified for the first 4 h exposure. Suggestive QTLs for sustained intake during later weeks were identified on Chrs 4 and 8. Thirty high priority candidate genes, including Entpd2, Per3, and Fto were nominated for early and sustained alcohol intake QTLs. In addition, a suggestive QTL on Chr 15 was detected for change in 2 h alcohol intake over the duration of the study and Adcy8 was identified as a strong candidate gene. Bioinformatic analyses revealed that early and sustained alcohol intake is likely driven by genes and pathways involved in signaling, and/or immune and metabolic function, while a combination of epigenetic factors related to alcohol experience and genetic factors likely drives progressive alcohol intake.

Highlights

According to Cloninger (1987) and Babor et al (1992) there are multiple types of alcohol use disorders and likely different genetic contributions to each type
The research that we present here is a continuation of these studies in which we report on initial early intake and sustained alcohol consumption over a 5-week period in 39 BXD strains using the “drinking in the dark” (DID) protocol described by Rhodes et al (2005)
Intake of 20% alcohol for 2 or 4 h during the first and 5th week was variable in female B6, D2, and 39 BXD strains (Figure 1)

Summary

Introduction

According to Cloninger (1987) and Babor et al (1992) there are multiple types of alcohol use disorders and likely different genetic contributions to each type. Over 10 brain regions have been subjected to microarray analysis of gene expression and there is a freely available database consisting of more than 5,000 phenotypes contributed by many laboratories This includes over 15 alcohol-related data sets in which the BXD family has been used to measure alcohol acceptance, consumption and preference (Phillips et al, 1994; Rodriguez et al, 1994; Gill et al, 1996; Fernandez et al, 1999); metabolism (Browman and Crabbe, 2000; Grisel et al, 2002; Philip et al, 2010); hypothermia, withdrawal, tolerance, and sensitivity (Belknap et al, 1993; Roberts et al, 1995; Crabbe et al, 1996; Phillips et al, 1996; Buck et al, 1997; Crabbe, 1998; Browman and Crabbe, 2000; Philip et al, 2010); locomotor response (Phillips et al, 1995; Browman and Crabbe, 2000; Philip et al, 2010); ethanol induced conditioned taste aversion (Risinger and Cunningham, 1998); and ethanol conditioned place preference (Cunningham, 1995). This family contributed to the most detailed meta-analysis of genes that contribute to the predisposition for high alcohol consumption (Mulligan et al, 2006)

Methods

Results

Conclusion