Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression.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.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.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.
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, University of Heidelberg, Germany. marcella.rietschel@zi-mannheim.de
%0 Journal Article
%1 Rietschel2010
%A Rietschel, Marcella
%A Mattheisen, Manuel
%A Frank, Josef
%A Treutlein, Jens
%A Degenhardt, Franziska
%A Breuer, René
%A Steffens, Michael
%A Mier, Daniela
%A Esslinger, Christine
%A Walter, Henrik
%A Kirsch, Peter
%A Erk, Susanne
%A Schnell, Knut
%A Herms, Stefan
%A Wichmann, H-Erich
%A Schreiber, Stefan
%A Jöckel, Karl-Heinz
%A Strohmaier, Jana
%A Roeske, Darina
%A Haenisch, Britta
%A Gross, Magdalena
%A Hoefels, Susanne
%A Lucae, Susanne
%A Binder, Elisabeth B.
%A Wienker, Thomas F.
%A Schulze, Thomas G.
%A Schmäl, Christine
%A Zimmer, Andreas
%A Juraeva, Dilafruz
%A Brors, Benedikt
%A Bettecken, Thomas
%A Meyer-Lindenberg, Andreas
%A Müller-Myhsok, Bertram
%A Maier, Wolfgang
%A Nöthen, Markus M.
%A Cichon, Sven
%D 2010
%J Biol Psychiatry
%K Adult; Aged; Association Brain, Carrier Depressive Disorder, Female; Genome-Wide Humans; Imaging; Magnetic Major, Male; Middle Performance, Proteins, Psychomotor Resonance Study, genetics/physiology; genetics/physiopathology/psychology; methods; physiology physiopathology;
%N 6
%P 578--585
%R 10.1016/j.biopsych.2010.05.038
%T Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression.
%U http://dx.doi.org/10.1016/j.biopsych.2010.05.038
%V 68
%X Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression.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.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.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.
@article{Rietschel2010,
__markedentry = {[bbrors:6]},
abstract = {Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression.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.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.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.},
added-at = {2015-04-09T12:36:21.000+0200},
author = {Rietschel, Marcella and Mattheisen, Manuel and Frank, Josef and Treutlein, Jens and Degenhardt, Franziska and Breuer, Ren{\'{e}} and Steffens, Michael and Mier, Daniela and Esslinger, Christine and Walter, Henrik and Kirsch, Peter and Erk, Susanne and Schnell, Knut and Herms, Stefan and Wichmann, H-Erich and Schreiber, Stefan and J{\"{o}}ckel, Karl-Heinz and Strohmaier, Jana and Roeske, Darina and Haenisch, Britta and Gross, Magdalena and Hoefels, Susanne and Lucae, Susanne and Binder, Elisabeth B. and Wienker, Thomas F. and Schulze, Thomas G. and Schm{\"{a}}l, Christine and Zimmer, Andreas and Juraeva, Dilafruz and Brors, Benedikt and Bettecken, Thomas and Meyer-Lindenberg, Andreas and M{\"{u}}ller-Myhsok, Bertram and Maier, Wolfgang and N{\"{o}}then, Markus M. and Cichon, Sven},
biburl = {https://www.bibsonomy.org/bibtex/269f0c64fc2edf703b2b6ae5883872e21/bbrors},
doi = {10.1016/j.biopsych.2010.05.038},
institution = {Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, University of Heidelberg, Germany. marcella.rietschel@zi-mannheim.de},
interhash = {4f0aa8dc630800249fa29d5408c1cdf2},
intrahash = {69f0c64fc2edf703b2b6ae5883872e21},
journal = {Biol Psychiatry},
keywords = {Adult; Aged; Association Brain, Carrier Depressive Disorder, Female; Genome-Wide Humans; Imaging; Magnetic Major, Male; Middle Performance, Proteins, Psychomotor Resonance Study, genetics/physiology; genetics/physiopathology/psychology; methods; physiology physiopathology;},
language = {eng},
medline-pst = {ppublish},
month = Sep,
number = 6,
owner = {bbrors},
pages = {578--585},
pii = {S0006-3223(10)00578-0},
pmid = {20673876},
timestamp = {2015-04-09T12:36:21.000+0200},
title = {Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression.},
url = {http://dx.doi.org/10.1016/j.biopsych.2010.05.038},
volume = 68,
year = 2010
}