Array allows for discovery of two new genetic loci previously undetected by microsatellite analysis, at higher speed and lower cost than a previous genome scan
Affymetrix reports that a team of researchers from Upstate Medical University, the Department of Veterans Affairs (VA), the University of Coimbra and the Broad and Whitehead Institutes discovered new evidence for whole genome linkage in bipolar disorder.
The study on this complex psychiatric disease is one of the first published using the GeneChip Mapping 10K array, a higher resolution, easier and faster alternative to microsatellites for linkage and linkage disequilibrium analyses. The study, which will be published in the May 2004 issue of the American Journal of Human Genetics, identified two new loci on chromosomes 6 and 11 that show evidence for linkage in this complex disorder.
Both loci contain genes that appear to play a major role in brain function, according to the paper.
The chromosome 6 finding replicated previous findings by the US National Institutes of Health (NIH), an encouraging step in a disease which often yields conflicting findings and unreproducible findings from study to study.
"This long-term genetic population study has the potential of helping us understand the importance of a variety of genetic factors on bipolar disorder and other psychotic disorders," explained Carlos and Michele Pato from Upstate Medical University and the Washington DC Veterans Affairs Medical Center.
"The ability to achieve genome-wide significance for linkage in this population was clearly enhanced by the far more complete linkage information possible with the 10K.
"We are looking forward to important collaborative efforts with others in the field to further explore these findings".
The study was performed in two parts.
In the first part, the research team analysed 12 families with both microsatellites and the Mapping 10K array.
The results showed a high degree of corresponding linkage findings for most chromosomes using both approaches.
More importantly, however, analysis with the Mapping 10K array showed evidence for significant genome-wide linkage on two additional chromosomes in locations where the marker density and information content of microsatellite-based assays were very low.
In the second part of the study, the analysis was expanded to include 25 families, all of which were assayed with the Mapping 10K.
These results demonstrated even greater evidence for genome-wide significance, with linkage mapping to chromosomal region 6q22.
This discovery, which replicated findings that took NIH researchers in bipolar disorder several years using hundreds of families, was arrived at in less than five months at about one tenth the cost of the previous microsatellite genome scan.
"Using the 10K clearly revealed gaps in the coverage and the information content of the traditional microsatellite-based assay," said Frank Middleton of Upstate Medical University.
"It was exactly in those gaps where the new significant signals were found. "We're very encouraged by the results, by the close correlation with the NIH findings, and by how fast and accurately we were able to do the study using the 10K array".
In planned follow-up studies, the research team will greatly expand the number of affected individuals studied, genotyping all families within the geographic area with histories of bipolar disorder using a similar whole genome approach.
In addition, the investigators will greatly increase the number of SNPs assayed in follow up analysis of the 6q22 linkage peaks and pool their results with data from the NIH showing a similar result.
The study was funded by the National Institute of Mental Health (NIMH), the VA, the National Alliance for Research on Schizophrenia and Depression (NARSAD), and the Fundacao para a Ciencia e a Tecnologia (FCT) in Portugal.
The Mapping 10K array brings whole genome SNP analysis to the benchtop by combining an innovative, scalable assay with a proven information platform. All 10,000 genotypes are generated in a single experiment, allowing more rapid discovery of genomic regions linked to disease.
The platform allows for automated genotype calling and produces the highest physical and genetic resolution available for family linkage studies in inherited disease.
Additional reported applications of this technology include cancer genetics (chromosomal amplification, deletion and loss of heterozygosity) and population genetics.
