Association of NPAS3 exonic variation with schizophrenia
Received 21 December 2009; received in revised form 5 April 2010; accepted 7 April 2010. published online 14 May 2010.
Abstract
Background
We previously identified the neuronal PAS3 (NPAS3) gene as a candidate gene for schizophrenia. A mother and daughter, both with schizophrenia, were carriers of a translocation, t(9;14)(q34;q13), that disrupts the NPAS3 gene. The gene is located at 14q13, a region implicated in schizophrenia and bipolar disorder in various linkage studies. NPAS3 belongs to the basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) transcription factor family, involved in diverse processes including the regulation of cell differentiation and circadian rhythms, and the development and function of the nervous system.
Methods
The 12 exons encoding NPAS3 were sequenced in DNA from individuals with schizophrenia. NPAS3 variants were identified in exons 6 and 12, initially in 12 patients only. These two exons were then sequenced in 83 patients and 83 controls.
Results and conclusion
Three common variants of NPAS3, also found in controls, showed a positive association with schizophrenia (NM_001164749: rs12434716, c.1654G>C, p=0.009; rs10141940, c.2208C>T, p=0.01; rs10142034, c.2262C>G, p=0.01). The c.1654G>C variant, results in an p.Ala552Pro change and may affect NPAS3 protein function directly. Alternatively, the three SNPs may affect the splicing of NPAS3 transcripts, as they are each located within putative exonic splicing enhancer (ESE) motifs (ESEFinder). A c.726C>T variant, identified in three patients, is located in an ESE element and is predicted to reduce the function of the motif. Other variants, identified in controls, included c.2089G>A (p.Gly697Ser) and c.2097T>C. Our identification of potentially defective NPAS3 variants supports recent studies that implicate perturbations in NPAS3 pathways in impaired neurogenesis and psychosis.
aDepartment of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7
bDepartment of Psychiatry and Bebensee Schizophrenia Research Unit, University of Alberta, Edmonton, Alberta, Canada, T6G 4R7
cCentre of Excellence in Neuromics of University of Montreal, CHUM Research Center and the Department of Medicine, University of Montreal, Montréal, Québec, Canada, H2L 4M1
Corresponding author. Department of Medical Genetics, 8-43B Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7. Tel.: +1 780 492 7501; fax: +1 780 492 1998.
1 Now at: Department of Psychiatry, Dalhousie University, Rm 3030, 3rd Floor, Abbie Lane Bldg, 5909 Veterans' Memorial Lane, Halifax, Nova Scotia, Canada, B3H 2E2.
ABSTRACT