Schizophrenia is a devastating disorder of unknown cause that affects about 1% of the U.S. population. The available treatments remain far from optimal, and the etiology and pathogenesis are unknown. Though the hereditability of schizophrenia may be as high as 80%, finding genetic risk factors has proven difficult. Over the past several years, great interest has arisen in the potential contribution of genomic copy number variation (CNV) to normal human traits and to disease, including schizophrenia. Recent findings using advances in array technology have shown that up to 12% of the human genome may be subject to variations in copy number. While it is now possible to detect copy number variations on whole genome SNP arrays, probes for these arrays have generally been selected to avoid repetitive regions, even though copy number variation is most likely to occur in precisely these regions. Short tandem repeats have emerged both as powerful markers for linkage studies and as mutations causing a number of human diseases. We hypothesize that polymorphisms of longer tandem repeats (unit length of 50 bp to >150,000 bp), relatively unexplored features of the human genome, may also contribute to normal human variation and to disease, including schizophrenia. To systematically address this issue, we propose to develop an oligonucleotide array specifically designed to detect changes in the number of repeating units in tandem repeats.
In Specific Aim 1, we will work with Dr. Evan Eichler of the Univ of Washington and the staff of NimbleGen, Inc to develop and preliminarily characterize an oligonucleotide array targeting >3000 tandem repeats.
In Specific Aim 2, we will preliminarily determine the extent of variation in these repeats in a heterogeneous U.S. control population and in 80 individuals with schizophrenia. Our overall goal is to sufficiently characterize the tandem repeat array so that it can be applied to large populations of patients (including, but not limited to, schizophrenia) to detect rare mutations of major effect on illness, and common variations that may make a minor contribution to disease risk. ? ? ?
| Bruce, Heather A; Sachs, Nancy; Rudnicki, Dobrila D et al. (2009) 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. Psychiatr Genet 19:64-71 |
