%0 Journal Article %J Cell %D 2011 %T Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. %A Klassen, Tara %A Davis, Caleb %A Goldman, Alica %A Burgess, Dan %A Chen, Tim %A Wheeler, David %A McPherson, John %A Bourquin, Traci %A Lewis, Lora %A Villasana, Donna %A Morgan, Margaret %A Muzny, Donna %A Gibbs, Richard %A Noebels, Jeffrey %K Computer Simulation %K Epilepsy %K Epistasis, Genetic %K Gene Expression Profiling %K Hippocampus %K Humans %K Ion Channels %K Mutation, Missense %K Neurons %K Polymorphism, Single Nucleotide %K Risk Assessment %X

Ion channel mutations are an important cause of rare Mendelian disorders affecting brain, heart, and other tissues. We performed parallel exome sequencing of 237 channel genes in a well-characterized human sample, comparing variant profiles of unaffected individuals to those with the most common neuronal excitability disorder, sporadic idiopathic epilepsy. Rare missense variation in known Mendelian disease genes is prevalent in both groups at similar complexity, revealing that even deleterious ion channel mutations confer uncertain risk to an individual depending on the other variants with which they are combined. Our findings indicate that variant discovery via large scale sequencing efforts is only a first step in illuminating the complex allelic architecture underlying personal disease risk. We propose that in silico modeling of channel variation in realistic cell and network models will be crucial to future strategies assessing mutation profile pathogenicity and drug response in individuals with a broad spectrum of excitability disorders.

%B Cell %V 145 %P 1036-48 %8 2011 Jun 24 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/21703448?dopt=Abstract %R 10.1016/j.cell.2011.05.025 %0 Journal Article %J Cancer Res %D 2011 %T Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium. %A Shete, Sanjay %A Lau, Ching C %A Houlston, Richard S %A Claus, Elizabeth B %A Barnholtz-Sloan, Jill %A Lai, Rose %A Il'yasova, Dora %A Schildkraut, Joellen %A Sadetzki, Siegal %A Johansen, Christoffer %A Bernstein, Jonine L %A Olson, Sara H %A Jenkins, Robert B %A Yang, Ping %A Vick, Nicholas A %A Wrensch, Margaret %A Davis, Faith G %A McCarthy, Bridget J %A Leung, Eastwood Hon-chiu %A Davis, Caleb %A Cheng, Rita %A Hosking, Fay J %A Armstrong, Georgina N %A Liu, Yanhong %A Yu, Robert K %A Henriksson, Roger %A Melin, Beatrice S %A Bondy, Melissa L %K Adolescent %K Adult %K Aged %K Brain Neoplasms %K Child %K Chromosome Mapping %K Family Health %K Female %K Genetic Heterogeneity %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Glioma %K Humans %K Linkage Disequilibrium %K Lod Score %K Male %K Middle Aged %K Pedigree %K Polymorphism, Single Nucleotide %K United States %K Young Adult %X

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma.

%B Cancer Res %V 71 %P 7568-75 %8 2011 Dec 15 %G eng %N 24 %1 https://www.ncbi.nlm.nih.gov/pubmed/22037877?dopt=Abstract %R 10.1158/0008-5472.CAN-11-0013 %0 Journal Article %J BMC Res Notes %D 2010 %T Bayesian estimation of genomic copy number with single nucleotide polymorphism genotyping arrays. %A Guo, Beibei %A Villagran, Alejandro %A Vannucci, Marina %A Wang, Jian %A Davis, Caleb %A Man, Tsz-Kwong %A Lau, Ching %A Guerra, Rudy %X

BACKGROUND: The identification of copy number aberration in the human genome is an important area in cancer research. We develop a model for determining genomic copy numbers using high-density single nucleotide polymorphism genotyping microarrays. The method is based on a Bayesian spatial normal mixture model with an unknown number of components corresponding to true copy numbers. A reversible jump Markov chain Monte Carlo algorithm is used to implement the model and perform posterior inference.

RESULTS: The performance of the algorithm is examined on both simulated and real cancer data, and it is compared with the popular CNAG algorithm for copy number detection.

CONCLUSIONS: We demonstrate that our Bayesian mixture model performs at least as well as the hidden Markov model based CNAG algorithm and in certain cases does better. One of the added advantages of our method is the flexibility of modeling normal cell contamination in tumor samples.

%B BMC Res Notes %V 3 %P 350 %8 2010 Dec 30 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/21192799?dopt=Abstract %R 10.1186/1756-0500-3-350 %0 Journal Article %J J Neurosci %D 2003 %T Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction. %A Powell, Elizabeth M %A Campbell, Daniel B %A Stanwood, Gregg D %A Davis, Caleb %A Noebels, Jeffrey L %A Levitt, Pat %K Animals %K Anxiety %K Behavior, Animal %K Calcium-Binding Proteins %K Cell Count %K Darkness %K Electroencephalography %K Epilepsy %K Exploratory Behavior %K GABA Antagonists %K gamma-Aminobutyric Acid %K Genetic Predisposition to Disease %K Interneurons %K Light %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Knockout %K Neocortex %K Receptors, Cell Surface %K Receptors, Urokinase Plasminogen Activator %K Spatial Behavior %X

The generation of properly functioning circuits during brain development requires precise timing of cell migration and differentiation. Disruptions in the developmental plan may lead to neurological and psychiatric disorders. Neocortical circuits rely on inhibitory GABAergic interneurons, the majority of which migrate from subcortical sources. We have shown that the pleiotropic molecule hepatocyte growth factor/scatter factor (HGF/SF) mediates interneuron migration. Mice with a targeted mutation of the gene encoding urokinase plasminogen activator receptor (uPAR), a key component in HGF/SF activation and function, have decreased levels of HGF/SF and a 50% reduction in neocortical GABAergic interneurons at embryonic and perinatal ages. Disruption of interneuron development leads to early lethality in most models. Thus, the long-term consequences of such perturbations are unknown. Mice of the uPAR-/- strain survive until adulthood, and behavior testing demonstrates that they have an increased anxiety state. The uPAR-/- strain also exhibits spontaneous seizure activity and higher susceptibility to pharmacologically induced convulsions. The neocortex of the adult uPAR-/- mouse exhibits a dramatic region- and subtype-specific decrease in GABA-immunoreactive interneurons. Anterior cingulate and parietal cortical areas contain 50% fewer GABAergic interneurons compared with wild-type littermates. However, interneuron numbers in piriform and visual cortical areas do not differ from those of normal mice. Characterization of interneuron subpopulations reveals a near complete loss of the parvalbumin subtype, with other subclasses remaining intact. These data demonstrate that a single gene mutation can selectively alter the development of cortical interneurons in a region- and cell subtype-specific manner, with deficits leading to long-lasting changes in circuit organization and behavior.

%B J Neurosci %V 23 %P 622-31 %8 2003 Jan 15 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/12533622?dopt=Abstract %R 10.1523/JNEUROSCI.23-02-00622.2003