Comprehensive analysis of genomic rare variants susceptible for psychiatric illnesses including schizophrenia

Research representative;Masanari Itokawa M.D.,Ph.D.,Schizophrenia &Affective Disorders Research Project,Tokyo Institute of Psychiatry
Research partaker;Makoto Arai Ph.D.,Schizophrenia &Affective Disorders Research Project,Tokyo Institute of Psychiatry
Research collaborator;Tomoe Ichikawa Ph.D.,Mitsuhiro Miyashita M.D.,Schizophrenia &Affective Disorders Research Project,Tokyo Institute of Psychiatry

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We analyze the full DNA sequence of all 46 chromosomes by utilizing next-generation sequencing system to detect rare variants accompanied with relative large functional alteration,which are investigated as a prototype of mental disease including schizophrenia to be generalized through common variations,and aim to reveal pathophysiology of psychiatric illnesses.  Our goal is to detect a relative small and homogeneous subgroup of schizophrenia sharing a rare variant with large effect since this study is performed on the assumption that schizophrenia is heterogeneous disease and is not done based upon the common disease-common variant hypothesis.

We resequenced genes that are coded in regions associated with schizophrenia according to linkage studies and found a novel frameshift mutation that an adenine was inserted in the first exon of glyoxalase 1 (GLO1).  The case carrying the mutation showed 50% reduced expression of mRNA,protein and enzymatic activity.  Advanced glycation end products (AGEs) that is synthesized from carbonyl compounds,which is a substrate of GLO1,was three times higher (carbonyl stress) and pyridoxamine (vitamin B6) was decreased by 82% in the case as compared with that of controls.  We measured plasma AGEs by using 45 schizophrenia and 61 controls since we suspected that there are another patients showing carbonyl stress.  AGEs levels were significantly increased in patient compared to that of controls (P<0.0001,OR=25.81) (Arai et al. Arch Gen Psychiatry 2010) (Figure).  We can detect relative homogeneous subgroup with carbonyl stress in schizophrenia by analyzing a carrier,as prototype of carbonyl stress induced schizophrenia,of the frameshift mutation concomitant with relative large genetic effect such as 50% reduction of enzymatic activity.  This study aims to reveal pathophysiology of schizophrenia by taking such approach.

This study was approved by ethical committee and written informed consent was obtained from the subjects.

Figure;Plasma AGEs (pentosidine) and serum vitamin B6 (pyrodoxal) levels in patients with schizophrenia and control subjects

(A) pentosidine levels (ng/ml),(B) pyridoxal levels (ng/ml),Reproduced from Arai et al. Arch Gen Psychiatry 67:589-597,2010