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

Abstract

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.

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Acknowledgements

We gratefully acknowledge the sequencing performed by the National Sequencing Core Facility, National Yang-Ming University, and the SNP genotyping performed by the National Center for Genome Medicine (NCGM), Taiwan. We thank Translational Resource Center for Genomic Medicine (TRC) of National Research Program for Biopharmaceuticals (NRPB) for their service. We also thank Taiwan Han Chinese Cell and Genome Bank of Academic Sinica for their support. Assistance was provided by the Microarray and SNP Core Facility for Genomic Medicine and the Department of Medical Research, National Taiwan University Hospital, and by Branch Office of Research and Development, National Taiwan University College of Medicine.

Funding

This work was supported by the National Research Program for Genomic Medicine (NRPGM), National Science Council and Ministry of Science, Taiwan [grant number NSC 97-3112-B-002- 046-, NSC 97-2321-B-002-041-, NSC 98-and 2321-B-002-008- to HGH; NSC 97-2314-B- 400-001-MY3 and NSC 101-2325-B-400-018 to HGH and CML; MOST 103-2325-B-002-047- and MOST 104-2314-B-002-068- to CML], the National Health Research Institute, Taiwan [grant number NHRI-EX-91, 92, 93-9113PP, MD095PP14, MD096PP12, MD097PP02, MD096PP12, MD097PP14, MD096SP01, and MD097SP01 to HGH], the National Institutes of Health, USA [grant number IR01 MH 59624-01 to MTT], and National Taiwan University [grant number 97HM00271~7 to HGH and CML]. The funding sources played no role in the design of the study, the collection, analysis, or interpretation of data, or the decision to submit this manuscript for publication.

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Correspondence to Chih-Min Liu.

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