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

Authors:
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
Year of publication:
2010
Volume:
68
Issue:
6
Issn:
0006-3223
Journal title abbreviated:
BIOL PSYCHIAT
Journal title long:
Biological psychiatry : a journal of psychiatric neuroscience : a publication of the Society of Biological Psychiatry
Impact factor:
11.212
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.