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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.* ; Haenisch, B.* ; Gross, M.* ; Hoefels, S.* ; Lucae, S.* ; Binder, E.B.* ; Wienker, T.F.* ; Schulze, T.G.* ; Schmäl, C.* ; Zimmer, A.* ; Juraeva, D.* ; Brors, B.* ; Bettecken, T.* ; Meyer-Lindenberg, A.* ; Müller-Myhsok, B.* ; Maier, W.* ; Nöthen, M.M.* ; Cichon, S.*

Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression.

Biol. Psychiatry 68, 589-601 (2010)

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Open Access Green as soon as Postprint is submitted to ZB.

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Carboxypeptidase M; CPM; gene-wide; HOMER1; major depression; neuroimaging; MACROPHAGE MATURATION; FRONTAL-CORTEX; SCHIZOPHRENIA; DISORDER; HERITABILITY; DYSFUNCTION; PARADIGM; GENETICS; DISEASE; LINKAGE

ISSN (print) / ISBN 0006-3223

e-ISSN 1873-2402

Journal Biological Psychiatry

Quellenangaben Volume: 68, Issue: 6, Pages: 589-601

Publisher Elsevier

Publishing Place New York, NY

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Epidemiology (EPI)