title: Polymorphisms within the metabotropic glutamate receptor 1 gene are associated with depression phenotypes.
abstract: OBJECTIVE
  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.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 10, D-80804 Munich, Germany. menke@mpipsykl.mpg.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Menke
authors.forename: Philipp
authors.initials: P
authors.lastname: Sämann
authors.forename: Stefan
authors.initials: S
authors.lastname: Kloiber
authors.forename: Darina
authors.initials: D
authors.lastname: Czamara
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.forename: Johannes
authors.initials: J
authors.lastname: Hennings
authors.forename: Angela
authors.initials: A
authors.lastname: Heck
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kohli
authors.forename: Michael
authors.initials: M
authors.lastname: Czisch
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003346:Corticotropin-Releasing Hormone; D003863:Depression / Q000235:genetics*; D003866:Depressive Disorder / Q000235:genetics*; D003907:Dexamethasone; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics / Q000523:psychology*; D005838:Genotype; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010912:Pituitary-Adrenal Function Tests / Q000379:methods / Q000523:psychology* / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone