title: Analysis of the effects of depression associated polymorphisms on the activity of the BICC1 promoter in amygdala neurones.
abstract: The Bicaudal C Homolog 1 (BICC1) gene, which encodes an RNA binding protein, has been identified by genome wide association studies (GWAS) as a candidate gene associated with major depressive disorder (MDD). We explored the hypothesis that MDD associated single-nucleotide polymorphisms (SNPs) affected the ability of cis-regulatory elements within intron 3 of the BICC1 gene to modulate the activity of the BICC1 promoter region. We initially established that the BICC1 promoter drove BICC1 mRNA expression in amygdala, hippocampus and hypothalamus. Intriguingly, we provide evidence that MDD associated polymorphisms alter the ability of the BICC1 promoter to respond to PKA signalling within amygdala neurones. Considering the known role of amygdala PKA pathways in fear learning and mood these observations suggest a possible mechanism through which allelic changes in the regulation of the BICC1 gene in amygdala neurones may contribute to mood disorders. Our findings also suggest a novel direction for the identification of novel drug targets and the design of future personalised therapeutics.The Pharmacogenomics Journal advance online publication, 6 October 2015; doi:10.1038/tpj.2015.62.
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
authors.forename: S
authors.initials: S
authors.lastname: Davidson
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
authors.forename: L
authors.initials: L
authors.lastname: Shanley
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
authors.forename: P
authors.initials: P
authors.lastname: Cowie
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
authors.forename: M
authors.initials: M
authors.lastname: Lear
authors.affiliation: Social, Genetic and Developmental Psychiatry Centre (MRC), Institute of Psychiatry, Psychology and Neuroscience, Denmark Hill, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: McGuffin
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Quinn
authors.affiliation: The Rowett Institute of Nutrition and Health, Bucksburn, Aberdeen, UK.
authors.forename: P
authors.initials: P
authors.lastname: Barrett
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
authors.forename: A
authors.initials: A
authors.lastname: MacKenzie
mesh_terms: D000339:Affect; D000679:Amygdala / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D019295:Computational Biology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D004789:Enzyme Activation; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
chemical_list: C571508:Bicc1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D017868:Cyclic AMP-Dependent Protein Kinases