Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression.
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.
Rietschel
Marcella
M
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, University of Heidelberg, Germany. marcella.rietschel@zi-mannheim.de
Mattheisen
Manuel
M
Frank
Josef
J
Treutlein
Jens
J
Degenhardt
Franziska
F
Breuer
René
R
Steffens
Michael
M
Mier
Daniela
D
Esslinger
Christine
C
Walter
Henrik
H
Kirsch
Peter
P
Erk
Susanne
S
Schnell
Knut
K
Herms
Stefan
S
Wichmann
H-Erich
HE
Schreiber
Stefan
S
Jöckel
Karl-Heinz
KH
Strohmaier
Jana
J
Roeske
Darina
D
Haenisch
Britta
B
Gross
Magdalena
M
Hoefels
Susanne
S
Lucae
Susanne
S
Binder
Elisabeth B
EB
Wienker
Thomas F
TF
Schulze
Thomas G
TG
Schmäl
Christine
C
Zimmer
Andreas
A
Juraeva
Dilafruz
D
Brors
Benedikt
B
Bettecken
Thomas
T
Meyer-Lindenberg
Andreas
A
Müller-Myhsok
Bertram
B
Maier
Wolfgang
W
Nöthen
Markus M
MM
Cichon
Sven
S
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
D002352:Carrier Proteins; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse