Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P = 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

No Evidence that Extended Tracts of Homozygosity are Associated with Alzheimer’s Disease.

We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease.

The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease

Rare mutations in AßPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AßPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.

Analysing admittance of obstacles in evanescent waveguide using the Imaginary Smith Chart

We present a technique, using the Imaginary Smith Chart, for determining the admittance of obstacles introduced into evanescent waveguide. The admittance of an inductive iris, capacitive iris, capacitive post, variable width strip and length of evanescent waveuide are investigated. © 2012 IEEE.

Increased Bandwidth Evanescent Open-Ended Waveguide Antenna Design Using the Imaginary Smith Chart

We present a novel antenna matching technique that uses the Imaginary Smith Chart to permit wideband matching of an evanescent open-ended waveguide antenna using a dielectric sheet air-spaced from the aperture. The fabricated antenna design is demonstrated to have a measured bandwidth of 24%, from 2.13–2.7 GHz, for reflection coefficient $qquad{<} -!!10~{rm dB}$ , with 2.725 GHz waveguide cutoff. The antenna's maximum aperture dimension is ${< 0.5}lambda_{0}$ at the upper frequency in the bandwidth and so it is suitable for use in a wide angle scanning phased array

Prevalence, phenomenology, aetiology and predictors of challenging behaviour in Smith-Magenis syndrome

Background

The prevalence, phenomenology aetiology and correlates of four forms of challenging behaviour in 32 children and adults with Smith-Magenis syndrome (SMS) were investigated.

Methods

Cognitive assessments, questionnaires and semi-structured interviews were used to gather data on intellectual disability, verbal and physical aggression, destructive behaviour and self-injury and on characteristics known to be associated with aggression.

Results

Aggression in SMS was more prevalent (87%), but not more severe than aggression in contrast groups. Aggressive behaviour was more frequently associated with environmental contingencies (e.g. attention, escape and access to tangibles) than self-injury and destructive behaviours. Severity of challenging behaviours was associated with high impulsivity.

Conclusion

Aggression is seen in the majority of people with SMS. Results suggest that behavioural disinhibition and operant social reinforcement are associated with the manifestation of aggression.

Causal Models of Clinically Significant Behaviors in Angelman, Cornelia de Lange, Prader-Willi and Smith-Magenis Syndromes

The operant learning theory account of behaviors of clinical significance in people with intellectual disability (ID) has dominated the field for nearly 50 years. However, in the last two decades, there has been a substantial increase in published research that describes the behavioral phenotypes of genetic disorders and shows that behaviors such as self-injury and aggression are more common in some syndromes than might be expected given group characteristics. These cross-syndrome differences in prevalence warrant explanation, not least because this observation challenges an exclusively operant learning theory account. To explore this possible conflict between theoretical account and empirical observation, we describe the genetic cause and physical, social, cognitive and behavioral phenotypes of four disorders associated with ID (Angleman, Cornelia de Lange, Prader-Willi and Smith-Magenis syndromes) and focus on the behaviors of clinical significance in each syndrome. For each syndrome we then describe a model of the interactions between physical characteristics, cognitive and motivational endophenotypes and environmental factors (including operant reinforcement) to account for the resultant behavioral phenotype. In each syndrome it is possible to identify pathways from gene to physical phenotype to cognitive or motivational endophenotype to behavior to environment and back to behavior. We identify the implications of these models for responsive and early intervention and the challenges for research in this area. We identify a pressing need for meaningful dialog between different disciplines to construct better informed models that can incorporate all relevant and robust empirical evidence.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Manual mapping of drumlins in synthetic landscapes to assess operator effectiveness

Mapped topographic features are important for understanding processes that sculpt the Earth’s surface. This paper presents maps that are the primary product of an exercise that brought together 27 researchers with an interest in landform mapping wherein the efficacy and causes of variation in mapping were tested using novel synthetic DEMs containing drumlins. The variation between interpreters (e.g. mapping philosophy, experience) and across the study region (e.g. woodland prevalence) opens these factors up to assessment. A priori known answers in the synthetics increase the number and strength of conclusions that may be drawn with respect to a traditional comparative study. Initial results suggest that overall detection rates are relatively low (34–40%), but reliability of mapping is higher (72–86%). The maps form a reference dataset.