Case-case genome-wide association analysis shows markers differentially associated with schizophrenia and bipolar disorder and implicates calcium channel genes.
ABSTRACT There are theoretical reasons why comparing marker allele frequencies between cases of different diseases, rather than with controls, may offer benefits. The samples may be better matched, especially for background risk factors common to both diseases. Genetic loci may also be detected which influence which of the two diseases occurs if common risk factors are present.
We used samples of UK bipolar and schizophrenic cases that had earlier been subject to genome-wide association studies and compared marker allele frequencies between the two samples. When these differed for a marker, we compared the case sample allele frequencies with those of a control sample.
Eight markers were significant at P value of less than 10(-5). Of these, the most interesting finding was for rs17645023, which was significant at P value of less than 10(-6) and which lies 36 kb from CACNG5. Control allele frequencies for this marker were intermediate between those for bipolar and schizophrenic cases.
The application of this approach suggests that it does have some merits. The finding for CACNG5, taken together with the earlier implication of CACNA1C and CACNA1B, strongly suggests a key role for voltage-dependent calcium channel genes in the susceptibility to bipolar disorder and/or schizophrenia.
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ABSTRACT: Using exome sequencing and linkage analysis in a 3-generation family with an unique dominant Mycolonus-Dystonia-like syndrome with cardiac arrhythmias we identified a mutation in the CACNA1B gene, coding for neuronal voltage-gated calcium channels CaV2.2. This mutation (c.4166G>A;p.Arg1389His) is a disruptive missense mutation in the outer region of the ion pore. The functional consequences of the identified mutation was studied using whole cell and single channel patch recordings. High resolution analyses at the single channel level showed that, when open, R1389H CaV2.2 channels carried less current compared to WT channels. Other biophysical channel properties were unaltered in R1389H channels including ion selectivity, voltage-dependent activation or voltage-dependent inactivation. CaV2.2 channels regulate transmitter release at inhibitory and excitatory synapses. Functional changes could be consistent with a gain-of-function causing the observed hyperexcitability characteristic of this unique Myoclonus-Dystonia-like syndrome associated with cardiac arrhythmias.Human Molecular Genetics 10/2014; · 6.68 Impact Factor
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ABSTRACT: Repetitive and redundant regions of a genome are particularly problematic for mapping sequencing reads. In the present paper, we compile a list of the unmappable regions in the human genome based on the following definition: hypothetical reads with length 1kb which cannot be uniquely mapped with zero-mismatch alignment for the described regions, considering both the forward and reverse strand. The respective collection of unmappable regions covers 0.77% of the sequence of human autosomes and 8.25% of the sex chromosomes in the reference genome GRCh37/hg19 (overall 1.23%). Not surprisingly, our unmappable regions overlap greatly with segmental duplication, transposable elements, and structural variants. About 99.8% of bases in our unmappable regions are part of either segmental duplication or transposable elements and 98.3% overlap structural variant annotations. Notably, some of these regions overlap units with important biological functions, including 4% of protein-coding genes. In contrast, these regions have zero intersection with the ultraconserved elements, very low overlap with microRNAs, tRNAs, pseudogenes, CpG islands, tandem repeats, microsatellites, sensitive non-coding regions, and the mapping blacklist regions from the ENCODE project.Computational Biology and Chemistry 08/2014; 53. · 1.60 Impact Factor
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ABSTRACT: Neurological channelopathies are attributed to aberrant ion channelsaffectingCNS, PNS, cardiac and skeletal muscles.To maintain thehomeostasis of excitable tissues; functional ion channels are necessary to rely electrical signalswhereas any malfunctioning serves as an intrinsic factor todevelop neurological channelopathies.Molecular basis of these disease arestudiedbased on genetic and biophysical approaches, e.g. loci positional cloning whereas pathogenesis and bio-behavioralanalysis revealed the dependency ongenetic mutations and inter-current triggering factors.Although, electrophysiological studies revealed the possible mechanisms of diseases but analytical study of ion channels remained unsettled and therefore underlying mechanism in channelopathies is necessary for better clinical application. Herein, we demonstrated (i) structural and functional role of various ion channels(Na+, K+, Ca2+,Cl-), (ii) pathophysiology involved in the onset of their associated channelopathies and (iii) comparative sequence and phylogenetic analysis of diversified sodium, potassium, calcium and chloride ion channel subtypes.Journal of Membrane Biology 07/2014; · 2.48 Impact Factor