Pathway analyses implicate glial cells in schizophrenia.

Background: The quest to understand the neurobiology of schizophrenia and bipolar disorder is ongoing with multiple lines of evidence indicating abnormalities of glia, mitochondria, and glutamate in both disorders. Despite high heritability estimates of 81% for schizophrenia and 75% for bipolar disorder, compelling links between findings from neurobiological studies, and findings from large-scale genetic analyses, are only beginning to emerge.

Method: Ten publically available gene sets (pathways) related to glia, mitochondria, and glutamate were tested for association to schizophrenia and bipolar disorder using MAGENTA as the primary analysis method.

Genetic modifiers and subtypes in schizophrenia: investigations of age at onset, severity, sex and family history.

Schizophrenia is a genetically and clinically heterogeneous disorder. Genetic risk factors for the disorder may differ between the sexes or between multiply affected families compared to cases with no family history. Additionally, limited data support a genetic basis for variation in onset and severity, but specific loci have not been identified.

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.

Reciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia.

Background: Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.

Multiplex target enrichment using DNA indexing for ultra-high throughput SNP detection.

Screening large numbers of target regions in multiple DNA samples for sequence variation is an important application of next-generation sequencing but an efficient method to enrich the samples in parallel has yet to be reported. We describe an advanced method that combines DNA samples using indexes or barcodes prior to target enrichment to facilitate this type of experiment. Sequencing libraries for multiple individual DNA samples, each incorporating a unique 6-bp index, are combined in equal quantities, enriched using a single in-solution target enrichment assay and sequenced in a single reaction.

Population structure and genome-wide patterns of variation in Ireland and Britain.

Located off the northwestern coast of the European mainland, Britain and Ireland were among the last regions of Europe to be colonized by modern humans after the last glacial maximum. Further, the geographical location of Britain, and in particular of Ireland, is such that the impact of historical migration has been minimal. Genetic diversity studies applying the Y chromosome and mitochondrial systems have indicated reduced diversity and an increased population structure across Britain and Ireland relative to the European mainland.

Ligand switching in cell-permeable peptides: manipulation of the alpha-integrin signature motif.

A synthetic cell-permeable peptide corresponding to the highly conserved alpha-integrin signature motif, Palmityl-K(989)VGFFKR(995) (Pal-FF), induces integrin activation and aggregation in human platelets. Systematic replacement of the F(992)-F(993) with amino acids of greater or lesser hydrophobicity to create Pal-KVGxxKR peptides demonstrate that hydrophobic amino acids (isoleucine, phenylalanine, tyrosine, tryptophan) are essential for agonist potency. In marked contrast, substitution with small and/or hydrophilic amino acids (glycine, alanine, serine) causes a switch in the biological activity resulting in inhibition of platelet aggregation, adhesion, ADP secretion, and thromboxane synthesis.

Non-random error in genotype calling procedures: implications for family-based and case-control genome-wide association studies.

The considerable data-handling requirements for genome wide association studies (GWAS) prohibit individual calling of genotypes and create a reliance on sophisticated "genotype-calling algorithms." Despite their obvious utility, the current genotyping platforms and calling-algorithms used are not without their limitations. Specifically, some genotypes are not called due to the ambiguity of the data.

Marked variation in predicted and observed variability of tandem repeat loci across the human genome.

Background: Tandem repeat (TR) variants in the human genome play key roles in a number of diseases. However, current models predicting variability are based on limited training sets. We conducted a systematic analysis of TRs of unit lengths 2-12 nucleotides in Whole Genome Shotgun (WGS) sequences to define the extent of variation of 209,214 unique repeat loci throughout the genome.

An assessment of the Irish population for large-scale genetic mapping studies involving epilepsy and other complex diseases.

The recent completion of the International HapMap Project has rapidly advanced our understanding of linkage disequilibrium (LD) in the human genome. Today, tagging SNPs (tSNPs) can be quickly and easily selected and consequently HapMap data are regularly applied to both small- and large-scale genetic mapping studies. However, to correctly interpret the application of HapMap-derived tSNPs in a genetic mapping study, an understanding of how well HapMap data represents LD in the study population is critical.

Tools for the identification of variable and potentially variable tandem repeats.

Background: Tandem repeat arrays showing variation between sequences within a population, between strains or across species may have functional effects. The increasing availability of genomic sequence data makes routine description of observed variation possible, creating a need for tools to describe such variability.

Results: We present a set of programs that facilitate the identification of tandem repeats showing variation across multiple sequences or genomes, and the prediction of potentially polymorphic tandem repeats.

Absolute net charge and the biological activity of oligopeptides.

Sequences of human proteins are frequently prepared as synthetic oligopeptides to assess their functional ability to act as compounds modulating pathways involving the parent protein. Our objective was to analyze a set of oligopeptides, to determine if their solubility or activity correlated with features of their primary sequence, or with features of properties inferred from three-dimensional structural models derived by conformational searches. We generated a conformational database for a set of 78 oligopeptides, derived from human proteins, and correlated their 3D structures with solubility and biological assay activity (as measured by platelet activation and inhibition).

Tandem repeat copy-number variation in protein-coding regions of human genes.

Background: Tandem repeat variation in protein-coding regions will alter protein length and may introduce frameshifts. Tandem repeat variants are associated with variation in pathogenicity in bacteria and with human disease. We characterized tandem repeat polymorphism in human proteins, using the UniGene database, and tested whether these were associated with host defense roles.