title: The CREB1-BDNF-NTRK2 pathway in depression: multiple gene-cognition-environment interactions.
abstract: BACKGROUND
  The neuroplastic pathway, which includes cyclic adenosine monophosphate response element-binding protein 1 (CREB1), brain-derived neurotrophic factor (BDNF), and its receptor (neurotrophic tyrosine kinase receptor, type 2 [NTRK2]), plays a crucial role in the adaptation of brain to stress, and thus variations of these genes are plausible risk factors for depression.
  
  
  METHODS
  A population-based sample was recruited, subsets of which were interviewed and underwent functional magnetic resonance imaging. We investigated the association of nine polymorphisms throughout the CREB1-BDNF-NTRK2 pathway with lifetime depression, rumination, current depression severity, negative life events, and sad face emotion processing in a three-level design.
  
  
  RESULTS
  In the population study, BDNF-rs6265 and CREB1-rs2253206 major alleles were significantly associated with rumination and through rumination with current depression severity. However, childhood adversity increased the risk of lifetime depression in the minor allele carriers of BDNF-rs6265 and CREB1-rs2253206 and in alleles of six other single nucleotide polymorphisms (SNPs). We validated our findings in the interviewed subjects using structural equation modeling. Finally, using functional magnetic resonance imaging, we found that viewing sad faces evoked greater activity in depression-related areas in healthy control subjects possessing the minor alleles of BDNF-rs6265 and CREB1-rs2253206.
  
  
  CONCLUSIONS
  Genetic variation associated with reduced function in the CREB1-BDNF-NTRK2 pathway has multiple, sometimes opposing, influences on risk mechanisms of depression, but almost all the SNPs studied amplified the effect of childhood adversity. The use of cognitive and neural intermediate phenotypes together with a molecular pathway approach may be critical to understanding how genes influence risk of depression.
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester, United Kingdom. gabriella.juhasz@manchester.ac.uk
authors.forename: Gabriella
authors.initials: G
authors.lastname: Juhasz
authors.forename: Jason S
authors.initials: JS
authors.lastname: Dunham
authors.forename: Shane
authors.initials: S
authors.lastname: McKie
authors.forename: Emma
authors.initials: E
authors.lastname: Thomas
authors.forename: Darragh
authors.initials: D
authors.lastname: Downey
authors.forename: Diana
authors.initials: D
authors.lastname: Chase
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lloyd-Williams
authors.forename: Zoltan G
authors.initials: ZG
authors.lastname: Toth
authors.forename: Hazel
authors.initials: H
authors.lastname: Platt
authors.forename: Krisztina
authors.initials: K
authors.lastname: Mekli
authors.forename: Antony
authors.initials: A
authors.lastname: Payton
authors.forename: Rebecca
authors.initials: R
authors.lastname: Elliott
authors.forename: Steve R
authors.initials: SR
authors.lastname: Williams
authors.forename: Ian M
authors.initials: IM
authors.lastname: Anderson
authors.forename: J F William
authors.initials: JF
authors.lastname: Deakin
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001921:Brain / Q000503:physiopathology; D001931:Brain Mapping; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D003866:Depressive Disorder / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008016:Life Change Events; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020813:Receptor, trkB / Q000235:genetics*; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D020813:Receptor, trkB