Genetic architecture controlling alcohol preference in rat lines divergently bred for alcohol-loving vs alcohol-avoiding behavior

Investigations on the influence of nature vs nurture on alcoholism (Alcohol Use Disorder) in human have yet to provide a clear view on potential genomic etiologies. To address this problems, authors [see attached paper] studied high (HAD) and low (LAD) alcohol-drinking rat lines that have been bred divergently as alcohol-loving and alcohol-avoiding phenotypes for >40 generations. The HAD/LAD lines were originally derived from the NIH heterogeneous stock (NIH-HS) and encompass genetic variation froman 8-way cross of inbred lines (similar to what Gerald McClearn did with mouse lines in the early 1970s). Rat HAD/LAD lines demonstrate a major heritable component for alcohol preference, providing an attractive model for researchers to uncover and understand the genetic and neurobiological bases that might underly human alcoholism and other AUDs.

 Authors carried out whole-genome sequencing (WGS) on 40 samples (10 per line of each replicate) to determine allele frequencies and haplotype blocks. Excessive differentiation in the genomic architecture between lines, across replicates––termed signatures of selection––were classified according to gene and region. Authors identified signatures of selection in 930 genes associated with alcohol preference. The majority (50%) of the signatures of selection were confined to single gene regions, the greatest numbers of which were in promoters (N=284) and intronic regions (N=169), with just four in exons, suggesting that differences in alcohol preference might be primarily due to alterations in regulatory regions.

 Authors confirmed previously identified genes and found many new genes associated with alcohol preference. Of those newly identified genes, several demonstrated neuronal function involved in synaptic memory and reward behavior (e.g. ion channels (Kcnf1, Kcnn3, Scn5a), excitatory receptors (Grin2a, Gria3, Grip1), neurotransmitters (Pomc), and synapses (Snap29). This study not only reveals the polygenic architecture of alcohol preference, but also emphasizes the importance of regulatory elements, consistent with other multifactorial traits.

PLoS Genet  2o16; 12: e1006178

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