COMT Val158Met genotype is associated with fluctuations in working memory performance: converging evidence from behavioural and single-trial P3b measures.

Intra-subject variability in reaction times (ISV) is a promising endophenotype for several psychiatric conditions, but its neural underpinnings are not yet established. Converging evidence from neuroimaging, molecular genetics, and psychopharmacology suggests that ISV could index catecholaminergically-mediated neural noise. The fine-grained temporal resolution of electroencephalography is ideal for investigating ISV, but only if potential neural correlates of ISV can be assessed in single trials. Based on evidence that ISV is associated with dopaminergic functioning, we apply a recently developed method of single-trial P3b analysis to investigate the association of COMT Val(158)Met genotype with measures of ISV on the behavioural and neural levels at different working memory loads. Greater number of Met alleles was associated with poorer and more intra-individually variable performance on the tasks, and greater latency jitter in single-trial P3bs. These converging results at the behavioural and neurophysiological levels confirm previous observations that prefrontal dopamine availability is associated with stability and accuracy of cognitive performance. Together with previous studies, these data imply pleiotropic cognitive effects of COMT genotype.

Mutation screening of the DTNBP1 exonic sequence in 669 schizophrenics and 710 controls using high-resolution melting analysis.

A large number of independent studies have reported evidence for association between the dysbindin gene (DTNBP1) and schizophrenia; however, specific risk alleles have been not been implicated as causal. In this study we set out to perform a comprehensive assessment of DNA variation within the exonic sequence of DTNBP1. To achieve this we optimized a high-resolution melting analysis (HRMA) protocol and applied it to screen all 11 DTNBP1 exons for DNA variants in a sample of 669 cases and 710 controls from the UK. Despite identifying seven exonic variants with a minor allele frequency (MAF) >0.01, none was significantly associated with schizophrenia (minimum P = 0.054), showing that the strong association we previously reported in this sample is not the result of association to a common functional variant located within the exonic sequence of any of the three major DTNBP1 transcripts. We also sought additional support for DTNBP1 as a susceptibility gene for schizophrenia by testing the hypothesis that rare exonic highly penetrant variants exist at the DTNBP1 locus. Our analysis failed to identify an enrichment of rare functional variants in the patients compared to the controls. Taken as a whole, this data demonstrate that if DTNBP1 is a risk gene for schizophrenia then risk is not conferred by mutations that affect the structure of the dysbindin protein.

Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH.

BACKGROUND: Segmental duplications flanking the neurofibromatosis type 1 (NF1) gene locus on 17q11 mediate most gene deletions in NF1 patients. However, the large size of the gene and the complexity of the locus architecture pose difficulties in deletion analysis. We report the construction and application of the first NF1 locus specific microarray, covering 2.24 Mb of 17q11, using a non-redundant approach for array design. The average resolution of analysis for the array is approximately 12 kb per measurement point with an increased average resolution of 6.4 kb for the NF1 gene. METHODS: We performed a comprehensive array-CGH analysis of 161 NF1 derived samples and identified heterozygous deletions of various sizes in 39 cases. The typical deletion was identified in 26 cases, whereas 13 samples showed atypical deletion profiles. RESULTS: The size of the atypical deletions, contained within the segment covered by the array, ranged from 6 kb to 1.6 Mb and their breakpoints could be accurately determined. Moreover, 10 atypical deletions were observed to share a common breakpoint either on the proximal or distal end of the deletion. The deletions identified by array-CGH were independently confirmed using multiplex ligation-dependent probe amplification. Bioinformatic analysis of the entire locus identified 33 segmental duplications. CONCLUSIONS: We show that at least one of these segmental duplications, which borders the proximal breakpoint located within the NF1 intron 1 in five atypical deletions, might represent a novel hot spot for deletions. Our array constitutes a novel and reliable tool offering significantly improved diagnostics for this common disorder.