title: Adenylate cyclase 7 is implicated in the biology of depression and modulation of affective neural circuitry.
abstract: BACKGROUND
  Evolutionarily conserved genes and their associated molecular pathways can serve as a translational bridge between human and mouse research, extending our understanding of biological pathways mediating individual differences in behavior and risk for psychopathology.
  
  
  METHODS
  Comparative gene array analysis in the amygdala and cingulate cortex between the serotonin transporter knockout mouse, a genetic animal model replicating features of human depression, and existing brain transcriptome data from postmortem tissue derived from clinically depressed humans was conducted to identify genes with similar changes across species (i.e., conserved) that may help explain risk of depressive-like phenotypes. Human neuroimaging analysis was then used to investigate the impact of a common single-nucleotide polymorphism (rs1064448) in a gene with identified conserved human-mouse changes, adenylate cyclase 7 (ADCY7), on threat-associated amygdala reactivity in two large independent samples.
  
  
  RESULTS
  Comparative analysis identified genes with conserved transcript changes in amygdala (n = 29) and cingulate cortex (n = 19), both critically involved in the generation and regulation of emotion. Selected results were confirmed by real-time quantitative polymerase chain reaction, including upregulation in the amygdala of transcripts for ADCY7, a gene previously implicated in human depression and associated with altered emotional responsiveness in mouse models. Translating these results back to living healthy human subjects, we show that genetic variation (rs1064448) in ADCY7 biases threat-related amygdala reactivity.
  
  
  CONCLUSIONS
  This converging cross-species evidence implicates ADCY7 in the modulation of mood regulatory neural mechanisms and, possibly, risk for and pathophysiology of depression, together supporting a continuous dimensional approach to major depressive disorder and other affective disorders.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Joeyen-Waldorf
authors.forename: Yuliya S
authors.initials: YS
authors.lastname: Nikolova
authors.forename: Nicole
authors.initials: N
authors.lastname: Edgar
authors.forename: Chris
authors.initials: C
authors.lastname: Walsh
authors.forename: Rama
authors.initials: R
authors.lastname: Kota
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.forename: Robert
authors.initials: R
authors.lastname: Ferrell
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Manuck
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Hariri
authors.forename: Etienne
authors.initials: E
authors.lastname: Sibille
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000328:Adult; D000679:Amygdala / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D003866:Depressive Disorder / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004644:Emotions / Q000502:physiology*; D005260:Female; D059907:Functional Neuroimaging / Q000379:methods / Q000523:psychology*; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006179:Gyrus Cinguli / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods / Q000523:psychology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; D000262:Adenylyl Cyclases; C473265:adenylyl cyclase 7