Reduced cortical thickness is associated with the glutamatergic regulatory gene risk variant DAOA Arg30Lys in schizophrenia

C. Christoph Schultz (1) , Igor Nenadic (1) , Kathrin Koch (1) , Gerd Wagner (1) , Martin Roebel (1) , Claudia Schachtzabel (1) , Thomas W Mühleisen (1) , Markus Nothen (1) , Sven Cichon (1) , Thomas Deufel (1) , Michael Kiehntopf (1) , Marcella Rietschel (1) , Juergen Reichenbach (1) , Heinrich Sauer (1) , Ralf Schlosser (1)

1 Department of Genomics, Life and Brain Center

Objective: In light of current etiological concepts the glutamatergic system plays an essential role for the pathophysiology of the disorder offering multiple options for new treatment strategies. The DAOA gene is closely connected to the glutamatergic system and its therapeutic and pathophysiological relevance for schizophrenia is therefore intensively debated. In a further step to shed light on the role of DAOA in schizophrenia we aimed to investigate the association of the functional DAOA Arg30Lys (rs2391191) variant and cortical thickness in schizophrenia. Methods: Cortical thickness was computed with an automated surface based technique (FreeSurfer) in 52 genotyped patients with schizophrenia and 42 healthy controls. Cortical thickness of the entire cortex was compared between risk carriers and non-risk carriers regarding the Arg30Lys polymorphism in patients and healthy controls on bases of a node by node procedure and an automated clustering approach. Results: Risk carriers with schizophrenia exhibit a significantly thinner cortex in two almost inversely arranged clusters on the left and right hemisphere comprising middle temporal, inferior parietal and lateral occipital cortical areas. The clusters encompass an area of 1174 mm² (left) and 1156 mm² (right). No significant effect was observed in healthy controls. Conclusions: The finding of our study that the Arg30Lys risk variant is associated with a distinct cortical thinning provides new evidence for the pathophysiological impact of DAOA in schizophrenia. The affected areas are mostly confined to cortical regions with a crucial role in the theory of mind network and visual processing, which both can be influenced via glutamatergic modulation. Our finding thus underlines the importance of DAOA and related glutamatergic processes as a putative target for therapeutic interventions in schizophrenia.

Mots clés: Neurogenetics; Biological Psychiatry; Imaging; Clinical or Preclinical; Glutamate; G72; DAOA; cortical thickness

C. Christoph Schultz, Igor Nenadic, Kathrin Koch, Gerd Wagner, Martin Roebel, et al.. Reduced cortical thickness is associated with the glutamatergic regulatory gene risk variant DAOA Arg30Lys in schizophrenia. Neuropsychopharmacology, 2011, ⟨10.1038/npp.2011.56⟩. ⟨hal-00633986⟩