Polymorphisms within the metabotropic glutamate receptor 1 gene are associated with depression phenotypes

Abstract

Objectives: Glutamate has been implicated in the pathophysiology and treatment of mood disorders possibly by affecting the regulation of the hypothalamus-pituitary-adrenocortical (HPA) axis. Growing evidence suggests an important role of the metabotropic glutamate receptor 1 (mGlu1) in depression-related phenotypes. To test whether these findings can also be supported by human genetics data, we explored polymorphisms within the metabotropic glutamate receptor 1 gene (GRM1) for their association with unipolar depression (UPD) as well as with biological phenotypes of this disorder.

Methods: We first tested the association of 43 tag-SNPs covering the GRM1 locus with UPD in 350 patients and 370 matched controls. We then investigated the effects of the associated SNPs on hippocampal glutamate levels estimated using ¹H-MR-spectroscopy (¹H-MRS) and on endocrine measures from the combined dexamethasone-suppression/CRH stimulation (dex/CRH) test.

Results: Within the GRM1 locus, 22 SNPs showed nominally significant association with UPD, of which 6 withstood corrections for multiple testing (rs2268666 with best allelic p=7.0×10⁻⁵). Supportive evidence for an association with UPD was gained from a second independent sample with 904 patients and 1012 controls. Furthermore, patients homozygous for the non-risk genotypes showed reduced hippocampal glutamate levels as measured by ¹H-MRS, a more pronounced normalization of HPA-axis hyperactivity as well as a better antidepressant treatment outcome.

Conclusions: These results suggest that the combination of genetic and biological markers may allow to subgroup patients into etiopathogenetically more relevant subcategories which could guide clinicians in their antidepressant treatment choices.