- 作者：Marcella Rietschel ; Manuel Mattheisen ; Josef Frank ; Jens Treutlein ; Franziska Degenhardt ; René ; Breuer ; Michael Steffens ; Daniela Mier ; Christine Esslinger ; Henrik Walter ; Peter Kirsch ; Susanne Er
- 关键词：Carboxypeptidase M ; CPM ; gene-wide ; HOMER1 ; major depression ; neuroimaging
- 刊名：Biological Psychiatry
- 出版年：2010
- 出版时间：15 September 2010
- 年：2010
- 卷：68
- 期：6
- 页码：578-585
- 全文大小：717 K
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.