ABSTRACT
Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.
Subject(s)
Schizophrenia/genetics , Adult , Case-Control Studies , Comparative Genomic Hybridization/methods , DNA Copy Number Variations/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Japan , Male , Polymorphism, Single Nucleotide/geneticsABSTRACT
We investigated influences on glycemic control in 177 diabetic patients after The Great Hanshin-Awaji Earthquake which occurred on January 17, 1995. Changes in serum HbA(1c) level were studied according to the worsen rate of dietary and living conditions. A significant temporary increase in the mean value of HbA(1c) level was found after the earthquake (8.34 +/- 2.07% in March, 1995 vs. 7.74 +/- 1.82% in December, 1994, P < 0.01). Ninety nine of them showed more than 0.5% in the rate of increase. Multiple regression analysis was applied to the following factors: inappropriate diet, discontinuation of drug uptake, reduction of exercise, destruction of house, long stay at shelter, sex, age, and pre-earthquake therapy. Among them, inappropriate diet demonstrated the highest partial regression coefficient to raise the mean value of the HbA(1c) level. The increased level of HbA(1c) declined gradually to the pre-earthquake level in September, 1995. This study emphasizes the importance of appropriate diet for diabetic patients during a natural disaster. To fulfil it, medical staff have to educate diabetic patients of their disorders tediously in ordinary time. In addition, it seems quite useful to supply a medical information card and a small medical bag containing essential drugs to each patient.
