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Methylation analysis of the NOTCH4 -25 C/T polymorphism in schizophrenia

McDonald, Patrick P.; O'Reilly, Richard; Singh, Shiva M.

doi: 10.1097/YPG.0b013e32834133bc
Original Articles

Background: The major histocompatability complex on chromosome 6p has often been identified as containing potential risk factors for schizophrenia. The NOTCH4 gene is located within this region (6p21.3) and sequence variants have previously shown association to the disease. It is further implicated from a functional standpoint as it plays a critical role during the neurodevelopmental process.

Methods: This research examined the methylation status of a region surrounding the NOTCH4 -25 C/T site in leukocyte genomic DNA and human brain regions. It also examined the polymorphism status of NOTCH4 -25 C/T. The sample included 40 individuals (16 affected, 24 controls) and 31 regions of an adult human brain (from a single individual).

Results: This study established that the -25 C was the only cytosine which showed methylation in any of the blood or brain samples analyzed. Furthermore, -25 C (i) was always fully or partially methylated in blood (ii) was methylated in a similar pattern between the affected and controls in the blood (iii) was variably methylated in the brain, including completely methylated, partially methylated, subtly methylated or not methylated. It also established that the -25 C/T polymorphism was not associated to schizophrenia.

Conclusion: The polymorphism and methylation analysis of NOTCH4 established that (i) the -25 C/T polymorphism and methylation status is not associated to schizophrenia in blood (ii) the -25 C is variably methylated in a region specific manner in the brain (iii) there is more variability observed within the brain of a single individual than in the blood among the individuals.

Department of Biology, Molecular Genetics Unit, Division of Medical Genetics, The University of Western Ontario, London, Ontario, Canada

Correspondence to Professor Shiva M. Singh, PhD, Department of Biology, Molecular Genetics Unit, Division of Medical Genetics, The University of Western Ontario, London, Ontario N6A 5B7, Canada Tel: +519 661 3135; fax: +519 661 3935; e-mail: ssingh@uwo.ca

Received February 2, 2010

Accepted May 8, 2010

© 2011 Lippincott Williams & Wilkins, Inc.