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Long tandem repeats as a form of genomic copy number variation: structure and length polymorphism of a chromosome 5p repeat in control and schizophrenia populations

Bruce, Heather A.a; Sachs, Nancya; Rudnicki, Dobrila D.a; Lin, Stephanie G.a; Willour, Virginia L.a; Cowell, John K.e; Conroy, Jeffreye; McQuaid, Devin E.e; Rossi, Michaele; Gaile, Daniel P.e; Nowak, Norma J.e; Holmes, Susan E.a; Sklar, Pamelag; Ross, Christopher A.a b c d; DeLisi, Lynn E.f; Margolis, Russell L.a b d

doi: 10.1097/YPG.0b013e3283207ff6
Original Articles

Objectives: Genomic copy number variations (CNVs) are a major form of variation in the human genome and play an etiologic role in several neuropsychiatric diseases. Tandem repeats, particularly with long (>50 bp) repeat units, are a relatively common yet underexplored type of CNV that may significantly contribute to human genomic variation and disease risk. We therefore carried out a pilot experiment to explore the potential role of long tandem repeats as risk factors in psychiatric disorders.

Methods: A bacterial artificial chromosome-based array comparative genomic hybridization (aCGH) platform was used to examine CNVs in genomic DNA from 34 probands with schizophrenia or schizoaffective disorder.

Results: The aCGH screen detected an apparent deletion on 5p15.1 in two probands, caused by the presence in each proband of two low copy number (short) alleles of a tandem repeat that ranges in length from fewer than 10 to greater than 50 3.4 kb units in the population examined. Short alleles partially segregate with schizophrenia in a small number of families, though linkage was not significant. An association study showed no significant difference in repeat length between 406 schizophrenia cases and 392 controls.

Conclusion: Although we did not demonstrate a relationship between the 5p15.1 repeat and schizophrenia, our results illustrate that long tandem repeats represent an intriguing type of genetic variation that have not been studied in earlier connection with psychiatric illness. aCGH can detect a small subset of these repeats, but systematic investigation will require the development of specific arrays and improved analytical methods.

Departments of aPsychiatry

bNeurology

cNeuroscience

dProgram in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland

eDepartment of Cancer Genetics, Roswell Park Cancer Institute, Buffalo

fDepartment of Psychiatry, New York University, New York

gPsychiatric Disease Initiative, Broad Institute of Massachusetts, Institute of Technology and Harvard University, Cambridge, Massachusetts, USA

Correspondence to Russell L Margolis, MD, CMSC 8-121, 600 N. Wolfe Street, Baltimore 21287, Maryland, USA

Tel: +1 410 614 4262; fax: +1 410 614 0013; e-mail: rmargoli@jhmi.edu

Present address: Nancy A. Sachs, Merck & Co., Inc., West Point, Pennsylvania; John K. Cowell, Medical College of Georgia, Augusta, Georgia; Michael Rossi, Emory University, Atlanta, Georgia; Lynn E. DeLisi, Brockton Virginia, Boston, Massachusetts.

Received 2 February 2008 Revised 1 August 2008 Accepted 29 August 2008

© 2009 Lippincott Williams & Wilkins, Inc.