Abstract
Using bacterial artificial chromosome (BAC) array comparative genome hybridization (aCGH) at approximately 1.4 Mbp resolution, we screened post-mortem brain DNA from bipolar disorder cases, schizophrenia cases and control individuals (n=35 each) for DNA copy-number aberrations. DNA copy number is a largely unexplored source of human genetic variation that may contribute risk for complex disease. We report aberrations at four loci which were seen in affected but not control individuals, and which were verified by quantitative real-time PCR. These aberrant loci contained the genes encoding EFNA5, GLUR7, CACNG2 and AKAP5; all brain-expressed proteins with known or postulated roles in neuronal function, and three of which (GLUR7, CACNG2 and AKAP5) are involved in glutamate signaling. A second cohort of psychiatric samples was also tested by quantitative PCR using the primer/probe sets for EFNA5, GLUR7, CACNG2 and AKAP5, and samples with aberrant copy number were found at three of the four loci (GLUR7, CACNG2 and AKAP5). Further scrutiny of these regions may reveal insights into the etiology and genetic risk factors for these complex psychiatric disorders.
Highlights
Bipolar disorder and schizophrenia are severe mental illnesses that affect thinking, mood and behavior and cause lifelong disability
In the initial screening phase, each of the 105 postmortem brain DNA samples was hybridized against a commercially available reference sample composed of pooled male genomic DNA from six individuals (Novagen)
A randomly chosen subset of these preliminary findings was evaluated by quantitative real-time PCR (Taqman, ABI), but only two of the 10 loci showed agreement between the two techniques and only one of these two loci contained a known brain-expressed protein (EFNA5 in bacterial artificial chromosome (BAC) clone RP11-252I13)
Summary
Bipolar disorder and schizophrenia are severe mental illnesses that affect thinking, mood and behavior and cause lifelong disability. Several chromosomal regions have been implicated as having genetic linkage in multiple studies [4] and finer scale mapping studies have narrowed these intervals and highlighted a number of candidate genes of small effect (5 – 9). Recent studies have highlighted DNA copy-number differences as a largely under-explored source of human genetic variation [10,11] that may be a common underlying factor in genetic disease [12]. Consistent with this notion, evaluation of DNA copy number in schizophrenia and bipolar disorder may yield insights into genetic risk factors for these diseases. Apart from the VCFS deletion, there are numerous reports of chromosomal
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