Reduced Cortical Thickness is Associated with the Glutamatergic Regulatory Gene Risk Variant DAOA Arg30Lys in Schizophrenia

Abstract

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 D-amino oxidase activator (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. Cortical thickness was computed by 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 the basis of a node-by-node procedure and an automated clustering approach. Risk carriers with schizophrenia show 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 mm 2 (left) and 1156 mm 2 (right). No significant effect was observed in healthy controls. 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 ToM network and visual processing, which both can be influenced by glutamatergic modulation. Our finding thus underlines the importance of DAOA and related glutamatergic processes as a putative target for therapeutic interventions in schizophrenia.

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Local brain gyrification as a marker of neurological soft signs in schizophrenia

“…To identify regions showing significant association between higher NSS levels and LGI, we used a hierarchical approach that minimizes the problem of multiple comparisons as described in prior publications [43,44]: As a first conservative procedure for the correction of Here, only those clusters that remained significant after Bonferroni correction will be discussed in detail.…”

Genetics of brain structure: Contributions from the vietnam era twin study of aging

“…There is evidence from studies in schizophrenia that potential risk genes may be preferentially related to either cortical thickness or area [Schultz et al, 2011; Kähler et al, 2012]. In addition, using surface maps of thickness and area expansion proved more powerful than ROI-based analyses in identifying shared and distinct abnormalities in schizophrenia and bipolar disorder [Rimol et al, 2012].…”