Variation at APOE and STH loci and Alzheimer's disease

BACKGROUND: The apolipoprotein E (APOE) and tau proteins play important roles in the pathological development of Alzheimer's disease (AD). Many studies have shown an association between the APOE gene and AD. Association between AD and the newly discovered saitohin (STH) gene, nested within the intron of the tau gene, has been reported. The present study aimed to elucidate the association between APOE and AD, and between STH and AD in our sample. METHODS: The functional polymorphisms, rs429358 and rs7412, in the APOE gene (which together define the ε2, ε3, and ε4 alleles), and the Q7R SNP in the STH gene, were genotyped in 369 patients with AD and 289 healthy European-Americans. The associations between these two genes and AD were analyzed in a case-control design. RESULTS: Consistent with previously reported results, the frequencies of the APOE ε4 allele, ε4/ε4 genotype and ε3/ε4 genotype were significantly higher in AD cases than controls; the ε4/ε4 genotype frequency was significantly higher in early-onset AD (EOAD) than late-onset AD (LOAD); the frequencies of the ε2 allele, ε3 allele, ε3/ε3 genotype and ε2/ε3 genotype were significantly lower in AD cases than controls. Positive likelihood ratios (LRs(+)) of APOE alleles and genotypes increased in a linear trend with the number of ε4 alleles and decreased in a linear trend with the number of ε2 or ε3 alleles. There was no significant difference in the STH allele and genotype frequency distributions between AD cases and controls. CONCLUSION: This study confirmed that the ε4 allele is a dose-response risk factor for AD and the ε4/ε4 genotype was associated with a significantly earlier age of onset. Moreover, we found that the ε2 allele was a dose-response protective factor for AD and the ε3 allele exerted a weaker dose-response protective effect for risk of AD compared with ε2. In a clinical setting, APOE genotyping could offer additional biological evidence of whether a subject may develop AD, but it is not robust enough to serve as an independent screening or predictive test in the diagnosis of AD. STH variation was not significantly associated with AD in our sample

Flexible and dynamic replication control for interdependent distributed real-time embedded systems

Replication is a proven concept for increasing the availability of distributed systems. However, actively replicating every software component in distributed embedded systems may not be a feasible approach. Not only the available resources are often limited, but also the imposed overhead could significantly degrade the system’s performance. This paper proposes heuristics to dynamically determine which components to replicate based on their significance to the system as a whole, its consequent number of passive replicas, and where to place those replicas in the network. The activation of passive replicas is coordinated through a fast convergence protocol that reduces the complexity of the needed interactions among nodes until a new collective global service solution is determined

Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk

Enhancing dependability through flexible adaptation to changing requirements

This paper describes an architectural approach that facilitates the dynamic adaptation of systems to changing domain rules. The approach relies on 'coordination contracts', a modelling and implementation primitive we have developed for run-time reconfiguration. Our framework includes an engine that, whenever a service is called, checks the domain rules that are applicable and configures the response of the service before proceeding with the call. This approach enhances dependability in two essential ways: on the one hand, it guarantees that system execution is always consistent with the domain logic because service response is configured automatically (i.e., without any need for programmer intervention); on the other hand, it makes it possible for changes to be incorporated into existing domain rules, and from new rules to be created, with little effort, because coordination contracts can be superposed dynamically without having to change neither the client nor the service code. Our approach is illustrated through a case study in financial systems, an area in which dependability arises mainly in the guise of business concerns like adherence to agreed policies and conditions negotiated on a case-by-case basis. We report on an information system that ATX Software developed for a company specialised in recovering bad credit. We show in particular how, by using this framework, we have devised a way of generating rule-dependent SQL code for batch-oriented services

Genome-wide association study of antisocial personality disorder diagnostic criteria provides evidence for shared risk factors across disorders

INTRODUCTION: While progress has been made in determining the genetic basis of antisocial behaviour, little progress has been made for antisocial personality disorder (ASPD), a condition that often co-occurs with other psychiatric conditions including substance use disorders, attention deficit hyperactivity disorder (ADHD), and anxiety disorders. This study aims to improve the understanding of the genetic risk for ASPD and its relationship with other disorders and traits. METHODS: We conducted a genome-wide association study (GWAS) of the number of ASPD diagnostic criteria data from 3217 alcohol-dependent participants recruited in the UK (UCL, N = 644) and the USA (Yale-Penn, N = 2573). RESULTS: We identified rs9806493, a chromosome 15 variant, that showed a genome-wide significant association (Z-score = -5.501, P = 3.77 × 10-8) with ASPD criteria. rs9806493 is an eQTL for SLCO3A1 (Solute Carrier Organic Anion Transporter Family Member 3A1), a ubiquitously expressed gene with strong expression in brain regions that include the anterior cingulate and frontal cortices. Polygenic risk score analysis identified positive correlations between ASPD and smoking, ADHD, depression traits, and posttraumatic stress disorder. Negative correlations were observed between ASPD PRS and alcohol intake frequency, reproductive traits, and level of educational attainment. CONCLUSION: This study provides evidence for an association between ASPD risk and SLCO3A1 and provides insight into the genetic architecture and pleiotropic associations of ASPD

Genome-wide association study identifies glutamate ionotropic receptor GRIA4 as a risk gene for comorbid nicotine dependence and major depression

Smoking and major depression frequently co-occur, at least in part due to shared genetic risk. However, the nature of the shared genetic basis is poorly understood. To detect genetic risk variants for comorbid nicotine dependence (ND) and major depression (MD), we conducted genome-wide association study (GWAS) in two samples of African-American participants (Yale-Penn 1 and 2) using linear mixed model, followed by meta-analysis. 3724 nicotine-exposed subjects were analyzed: 2596 from Yale-Penn-1 and 1128 from Yale-Penn-2. Continuous measures (Fagerström Test for Nicotine Dependence (FTND) scores and DSM-IV MD criteria) rather than disorder status were used to maximize the power of the GWAS. Genotypes were ascertained using the Illumina HumanOmni1-Quad array (Yale-Penn-1 sample) or the Illumina HumanCore Exome array (Yale-Penn-2 sample), followed by imputation based on the 1000 Genomes reference panel. An intronic variant at the GRIA4 locus, rs68081839, was significantly associated with ND-MD comorbidity (β = 0.69 [95% CI, 0.43-0.89], P = 1.53 × 10-8). GRIA4 encodes an AMPA-sensitive glutamate receptor that mediates fast excitatory synaptic transmission and neuroplasticity. Conditional analyses revealed that the association was explained jointly by both traits. Enrichment analysis showed that the top risk genes and genes co-expressed with GRIA4 are enriched in cell adhesion, calcium ion binding, and synapses. They also have enriched expression in the brain and they have been implicated in the risk for other neuropsychiatric disorders. Further research is needed to determine the replicability of these findings and to identify the biological mechanisms through which genetic risk for each condition is conveyed

Engineering Semantic Self-composition of Services Through Tuple-Based Coordination

Service self-composition is a well-understood research area focusing on service-based applications providing new services by automatically combining pre-existing ones. In this paper we focus on tuple-based coordination, and propose a solution leveraging logic tuples and tuple spaces to support semantic self-composition for services. A full-stack description of the solution is provided, ranging from a theoretical formalisation to a technologically valuable design and implementation

Genetic risk prediction and neurobiological understanding of alcoholism

We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value single-nucleotide length polymorphisms (SNPs) in the top candidate genes discovered by CFG (n = 135 genes, 713 SNPs) was used to generate a genetic risk prediction score (GRPS), which showed a trend towards significance (P = 0.053) in separating alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n = 11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P = 0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P = 0.00012) and one with alcohol abuse (a less severe form of alcoholism; P = 0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P = 0.000013) and the alcohol abuse cohort (P = 0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape