Genome-Wide Association-, Replication-, and Neuroimaging Study Implicates HOMER1 in the Etiology of Major Depression

被引：145

作者：

Rietschel, Marcella ^{[1
]}

Mattheisen, Manuel ^{[2
,3
,4
]}

Frank, Josef ^{[1
]}

Treutlein, Jens ^{[1
]}

Degenhardt, Franziska ^{[2
,3
]}

Breuer, Rene ^{[1
]}

Steffens, Michael ^{[4
]}

Mier, Daniela ^{[5
]}

Esslinger, Christine ^{[5
]}

Walter, Henrik ^{[6
]}

Kirsch, Peter ^{[5
]}

Erk, Susanne ^{[6
]}

Schnell, Knut ^{[6
]}

Herms, Stefan ^{[2
,3
]}

Wichmann, H. -Erich ^{[7
,8
,9
]}

Schreiber, Stefan ^{[10
,11
]}

Joeckel, Karl-Heinz ^{[12
]}

Strohmaier, Jana ^{[1
]}

Roeske, Darina ^{[13
]}

Haenisch, Britta ^{[2
,3
]}

Gross, Magdalena ^{[14
]}

Hoefels, Susanne ^{[14
]}

Lucae, Susanne ^{[13
]}

Binder, Elisabeth B. ^{[13
]}

Wienker, Thomas F. ^{[4
]}

Schulze, Thomas G. ^{[15
]}

Schmael, Christine ^{[1
]}

Zimmer, Andreas ^{[16
]}

Juraeva, Dilafruz ^{[17
]}

Brors, Benedikt ^{[17
]}

Bettecken, Thomas ^{[13
]}

Meyer-Lindenberg, Andreas ^{[5
]}

Mueller-Myhsok, Bertram ^{[13
]}

Maier, Wolfgang ^{[14
]}

Noethen, Markus M. ^{[2
,3
]}

Cichon, Sven ^{[2
,3
,18
]}

机构：

[1] Heidelberg Univ, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-68159 Mannheim, Germany

[2] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany

[3] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany

[4] Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-5300 Bonn, Germany

[5] Heidelberg Univ, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, D-68159 Mannheim, Germany

[6] Univ Bonn, Dept Psychiat & Psychotherapy, Div Med Psychol, D-5300 Bonn, Germany

[7] German Res Ctr Environm Hlth, Helmholtz Zentrum, Inst Epidemiol, Neuherberg, Germany

[8] Univ Munich, Inst Med Informat, Chair Epidemiol, Munich, Germany

[9] Munich Univ Hosp Campus Grosshadern, Munich, Germany

[10] Univ Kiel, Inst Clin Mol Biol, D-24098 Kiel, Germany

[11] Univ Kiel, Dept Gen Internal Med, D-24098 Kiel, Germany

[12] Univ Essen Gesamthsch, Inst Med Informat, Heinz Nixdorf Study Grp, Essen, Germany

[13] Max Planck Inst Psychiat, D-80804 Munich, Germany

[14] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany

[15] NIMH, Bethesda, MD 20892 USA

[16] Univ Bonn, Inst Mol Psychiat, D-5300 Bonn, Germany

[17] German Canc Res Ctr, D-6900 Heidelberg, Germany

[18] Struct & Funct Org Brain, Res Ctr, Inst Neurosci & Med, Julich, Germany

来源：

BIOLOGICAL PSYCHIATRY | 2010年 / 68卷 / 06期

关键词：

Carboxypeptidase M; CPM; gene-wide; HOMER1; major depression; neuroimaging; FRONTAL-CORTEX; DYSFUNCTION; PARADIGM; DISORDER; LINKAGE; MARKER; REWARD;

D O I：

10.1016/j.biopsych.2010.05.038

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 HOMER I. 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.

引用

页码：578 / 585

页数：8

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