title: High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model.
abstract: 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 issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol preference (AP). This model is uniquely suited to map genetic effects with high reproducibility, and resolution. The origin of the rat lines (an 8-way cross) resulted in small haplotype blocks (HB) with a corresponding high level of resolution. We sequenced DNAs from 40 samples (10 per line of each replicate) to determine allele frequencies and HB. We achieved ~46X coverage per line and replicate. Excessive differentiation in the genomic architecture between lines, across replicates, termed signatures of selection (SS), were classified according to gene and region. We identified SS in 930 genes associated with AP. The majority (50%) of the SS were confined to single gene regions, the greatest numbers of which were in promoters (284) and intronic regions (169) with the least in exon's (4), suggesting that differences in AP were primarily due to alterations in regulatory regions. We confirmed previously identified genes and found many new genes associated with AP. 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 AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits.
authors.affiliation: Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.|Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Chiao-Ling
authors.initials: CL
authors.lastname: Lo
authors.affiliation: Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.|Department of Animal Sciences, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Amy C
authors.identifier: 0000-0001-5078-7743
authors.initials: AC
authors.lastname: Lossie
authors.affiliation: Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.|Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Tiebing
authors.initials: T
authors.lastname: Liang
authors.affiliation: Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.|Department of Medical Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.|Department of Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Xiaoling
authors.identifier: 0000-0002-4143-2024
authors.initials: X
authors.lastname: Xuei
authors.affiliation: Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.|Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lumeng
authors.affiliation: Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.|Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.|Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Feng C
authors.initials: FC
authors.lastname: Zhou
authors.affiliation: Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.|Department of Animal Sciences, Purdue University, West Lafayette, Indiana, United States of America.|Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Muir
mesh_terms: D000437:Alcoholism / Q000235:genetics* / Q000503:physiopathology; D000438:Alcohols / Q000633:toxicity; D000818:Animals; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D023281:Genomics; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D020412:Multifactorial Inheritance / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D010641:Phenotype; D051381:Rats; D012641:Selection, Genetic
chemical_list: D000438:Alcohols