Genome-wide association-, replication-, and neuroimaging study implicates homer1 in the etiology of major depression

Marcella Rietschel; Manuel Mattheisen; Josef Frank; Jens Treutlein; Franziska Degenhardt; René Breuer; Michael Steffens; Daniela Mier; Christine Esslinger; Henrik Walter; Peter Kirsch; Susanne Erk; Knut Schnell; Stefan Herms; H. Erich Wichmann; Stefan Schreiber; Karl Heinz Jöckel; Jana Strohmaier; Darina Roeske; Britta Haenisch; Magdalena Gross; Susanne Hoefels; Susanne Lucae; Elisabeth B. Binder; Thomas F. Wienker; Thomas G. Schulze; Christine Schmäl; Andreas Zimmer; Dilafruz Juraeva; Benedikt Brors; Thomas Bettecken; Andreas Meyer-Lindenberg; Bertram Müller-Myhsok; Wolfgang Maier; Markus M. Nöthen; Sven Cichon

doi:10.1016/j.biopsych.2010.05.038

Genome-wide association-, replication-, and neuroimaging study implicates homer1 in the etiology of major depression

Marcella Rietschel, Manuel Mattheisen, Josef Frank, Jens Treutlein, Franziska Degenhardt, René Breuer, Michael Steffens, Daniela Mier, Christine Esslinger, Henrik Walter, Peter Kirsch, Susanne Erk, Knut Schnell, Stefan Herms, H. Erich Wichmann, Stefan Schreiber, Karl Heinz Jöckel, Jana Strohmaier, Darina Roeske, Britta HaenischMagdalena Gross, Susanne Hoefels, Susanne Lucae, Elisabeth B. Binder, Thomas F. Wienker, Thomas G. Schulze, Christine Schmäl, Andreas Zimmer, Dilafruz Juraeva, Benedikt Brors, Thomas Bettecken, Andreas Meyer-Lindenberg, Bertram Müller-Myhsok, Wolfgang Maier, Markus M. Nöthen, Sven Cichon

Research output: Contribution to journal › Article › peer-review

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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. Conclusion: 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.

Original language	English (US)
Pages (from-to)	578-585
Number of pages	8
Journal	Biological Psychiatry
Volume	68
Issue number	6
DOIs	https://doi.org/10.1016/j.biopsych.2010.05.038
State	Published - Sep 15 2010
Externally published	Yes

Keywords

Carboxypeptidase M
CPM
gene-wide
HOMER1
major depression
neuroimaging

ASJC Scopus subject areas

Biological Psychiatry

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10.1016/j.biopsych.2010.05.038

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Rietschel, M., Mattheisen, M., Frank, J., Treutlein, J., Degenhardt, F., Breuer, R., Steffens, M., Mier, D., Esslinger, C., Walter, H., Kirsch, P., Erk, S., Schnell, K., Herms, S., Wichmann, H. E., Schreiber, S., Jöckel, K. H., Strohmaier, J., Roeske, D., ... Cichon, S. (2010). Genome-wide association-, replication-, and neuroimaging study implicates homer1 in the etiology of major depression. Biological Psychiatry, 68(6), 578-585. https://doi.org/10.1016/j.biopsych.2010.05.038

Rietschel, M, Mattheisen, M, Frank, J, Treutlein, J, Degenhardt, F, Breuer, R, Steffens, M, Mier, D, Esslinger, C, Walter, H, Kirsch, P, Erk, S, Schnell, K, Herms, S, Wichmann, HE, Schreiber, S, Jöckel, KH, Strohmaier, J, Roeske, D, Haenisch, B, Gross, M, Hoefels, S, Lucae, S, Binder, EB, Wienker, TF, Schulze, TG, Schmäl, C, Zimmer, A, Juraeva, D, Brors, B, Bettecken, T, Meyer-Lindenberg, A, Müller-Myhsok, B, Maier, W, Nöthen, MM & Cichon, S 2010, 'Genome-wide association-, replication-, and neuroimaging study implicates homer1 in the etiology of major depression', Biological Psychiatry, vol. 68, no. 6, pp. 578-585. https://doi.org/10.1016/j.biopsych.2010.05.038

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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 (pcombined = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (pcombined = 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 (pcombined = 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. Conclusion: 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.",

keywords = "Carboxypeptidase M, CPM, gene-wide, HOMER1, major depression, neuroimaging",

author = "Marcella Rietschel and Manuel Mattheisen and Josef Frank and Jens Treutlein and Franziska Degenhardt and Ren{\'e} Breuer and Michael Steffens and Daniela Mier and Christine Esslinger and Henrik Walter and Peter Kirsch and Susanne Erk and Knut Schnell and Stefan Herms and Wichmann, {H. Erich} and Stefan Schreiber and J{\"o}ckel, {Karl Heinz} and Jana Strohmaier and Darina Roeske and Britta Haenisch and Magdalena Gross and Susanne Hoefels and Susanne Lucae and Binder, {Elisabeth B.} and Wienker, {Thomas F.} and Schulze, {Thomas G.} and Christine Schm{\"a}l and Andreas Zimmer and Dilafruz Juraeva and Benedikt Brors and Thomas Bettecken and Andreas Meyer-Lindenberg and Bertram M{\"u}ller-Myhsok and Wolfgang Maier and N{\"o}then, {Markus M.} and Sven Cichon",

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doi = "10.1016/j.biopsych.2010.05.038",

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T1 - Genome-wide association-, replication-, and neuroimaging study implicates homer1 in the etiology of major depression

AU - Rietschel, Marcella

AU - Mattheisen, Manuel

AU - Frank, Josef

AU - Treutlein, Jens

AU - Degenhardt, Franziska

AU - Breuer, René

AU - Steffens, Michael

AU - Mier, Daniela

AU - Esslinger, Christine

AU - Walter, Henrik

AU - Kirsch, Peter

AU - Erk, Susanne

AU - Schnell, Knut

AU - Herms, Stefan

AU - Wichmann, H. Erich

AU - Schreiber, Stefan

AU - Jöckel, Karl Heinz

AU - Strohmaier, Jana

AU - Roeske, Darina

AU - Haenisch, Britta

AU - Gross, Magdalena

AU - Hoefels, Susanne

AU - Lucae, Susanne

AU - Binder, Elisabeth B.

AU - Wienker, Thomas F.

AU - Schulze, Thomas G.

AU - Schmäl, Christine

AU - Zimmer, Andreas

AU - Juraeva, Dilafruz

AU - Brors, Benedikt

AU - Bettecken, Thomas

AU - Meyer-Lindenberg, Andreas

AU - Müller-Myhsok, Bertram

AU - Maier, Wolfgang

AU - Nöthen, Markus M.

AU - Cichon, Sven

PY - 2010/9/15

Y1 - 2010/9/15

N2 - 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 (pcombined = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (pcombined = 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 (pcombined = 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. Conclusion: 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.

AB - 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 (pcombined = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (pcombined = 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 (pcombined = 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. Conclusion: 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.

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KW - HOMER1

KW - major depression

KW - neuroimaging

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Genome-wide association-, replication-, and neuroimaging study implicates homer1 in the etiology of major depression

Abstract

Keywords

ASJC Scopus subject areas

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