title: Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression.
abstract: BACKGROUND
  Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression.
  
  
  METHODS
  We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects.
  
  
  RESULTS
  Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 (p(combined) = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (p(combined) = 1.48E-6), located in a putative regulatory region of HOMER1. Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 (p(combined) = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consistent with the findings of our subsequent human imaging genetics study, which revealed that variation in single nucleotide polymorphism rs7713917 had a significant influence on prefrontal activity during executive cognition and anticipation of reward.
  
  
  CONCLUSIONS
  Our findings, combined with evidence from preclinical and animal studies, suggest that HOMER1 plays a role in the etiology of major depression and that the genetic variation affects depression via the dysregulation of cognitive and motivational processes.
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, University of Heidelberg, Germany. marcella.rietschel@zi-mannheim.de
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.forename: Josef
authors.initials: J
authors.lastname: Frank
authors.forename: Jens
authors.initials: J
authors.lastname: Treutlein
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.forename: René
authors.initials: R
authors.lastname: Breuer
authors.forename: Michael
authors.initials: M
authors.lastname: Steffens
authors.forename: Daniela
authors.initials: D
authors.lastname: Mier
authors.forename: Christine
authors.initials: C
authors.lastname: Esslinger
authors.forename: Henrik
authors.initials: H
authors.lastname: Walter
authors.forename: Peter
authors.initials: P
authors.lastname: Kirsch
authors.forename: Susanne
authors.initials: S
authors.lastname: Erk
authors.forename: Knut
authors.initials: K
authors.lastname: Schnell
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Jöckel
authors.forename: Jana
authors.initials: J
authors.lastname: Strohmaier
authors.forename: Darina
authors.initials: D
authors.lastname: Roeske
authors.forename: Britta
authors.initials: B
authors.lastname: Haenisch
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gross
authors.forename: Susanne
authors.initials: S
authors.lastname: Hoefels
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Schulze
authors.forename: Christine
authors.initials: C
authors.lastname: Schmäl
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Dilafruz
authors.initials: D
authors.lastname: Juraeva
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Thomas
authors.initials: T
authors.lastname: Bettecken
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
mesh_terms: D000328:Adult; D001921:Brain / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D003865:Major Depressive Disorder / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D000072233:Homer Scaffolding Proteins; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011597:Psychomotor Performance / Q000502:physiology
chemical_list: D002352:Carrier Proteins; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse