Genetic associations and expression of extra-short isoforms of disrupted-in-schizophrenia 1 in a neurocognitive subgroup of schizophrenia.

Autor: Liu CM; Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. cmliu1968@ntu.edu.tw.; Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan. cmliu1968@ntu.edu.tw., Liu YL; Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan., Hwu HG; Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan., Fann CS; Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan., Yang UC; Institute of Bioinformatics, National Yang-Ming University, Taipei, Taiwan., Hsu PC; Institute of Bioinformatics, National Yang-Ming University, Taipei, Taiwan., Chang CC; Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan., Chen WJ; Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan., Hwang TJ; Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.; Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan., Hsieh MH; Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan., Liu CC; Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan., Chien YL; Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan., Lin YT; Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan., Tsuang MT; Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.; Harvard Departments of Epidemiology and Psychiatry, Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, USA.; Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Jazyk: angličtina
Zdroj: Journal of human genetics [J Hum Genet] 2019 Jul; Vol. 64 (7), pp. 653-663. Date of Electronic Publication: 2019 Apr 11.
DOI: 10.1038/s10038-019-0597-1
Abstrakt: Disrupted-in-schizophrenia 1 (DISC1) was reported to be associated with schizophrenia. In a previous study, we found significant association with schizophrenia patients with deficient sustained attention assessed by continuous performance test (CPT). This study aimed to identify risk polymorphisms in this specific neurocognitive subgroup and investigate the expression of different isoforms of DISC1. A total of 83 genetic variants were identified through direct sequencing in 50 controls and 100 schizophrenia patients. Fourteen variants were genotyped in 600 controls and 912 patients. Patients were subgrouped by familial loading (multiplex or simplex) and performance on CPT. The frequency of AA genotype of rs11122324 at the 3'-UTR of Es and Esv1 isoforms and of rs2793091 at intron 4 were significantly higher in multiplex schizophrenia patients than those in controls (corrected p < 0.05). In further subgrouping, the frequency of AA genotype of the two SNPs were significantly higher in multiplex schizophrenia patients with deficient sustained attention than those in controls (corrected p < 0.005). The mRNA expression levels of two extra-short isoforms (Es and Esv1) in the EBV-transformed lymphocytes of schizophrenia were significantly higher than those of controls. Luciferase reporter assays demonstrated that the A-allele of rs11122324 significantly upregulated DISC1 extra-short isoforms transcription compared with the G-allele. We found two SNPs (rs11122324 and rs2793091) of DISC1 may be specifically associated with multiplex schizophrenia patients with deficient sustained attention. The SNP rs11122324 may be a risk polymorphism, which may have functional influence on the transcription of Es and Esv1 through increasing their expression.
Databáze: MEDLINE
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