Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits

INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets

Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset

Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline

Neurodegenerative parkinsonism and progressive external ophthalmoplegia with a Twinkle mutation

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P-III: A Player-Centered, Iterative, Interdisciplinary and Integrated Framework for Serious Game Design and Development

While reconciling a creative game design process with a complex software engineering process is already a daunting task, serious games add another ingredient to an already volatile mixture: the challenge of crafting an effective learning experience. In order to achieve this strenuous objective, Group T's e-Media Lab and the Centre for User Experience Research, K.U.Leuven, have developed a player-centered, iterative, interdisciplinary and integrated (P-III) framework. This framework has been developed over the course of five years of research on the design and development of serious games. Hence, P-III is built bottom-up, molded and shaped, tested and refined through several research projects [1,9,17,18,19,20,21,22,23]. While P-III also prescribes a specific process, in this paper we limit ourselves to highlighting the four pillars of the P-III framework, and their theoretical underpinnings. © 2012 Springer-Verlag.status: publishe

The efficacy of a serious game aimed at the promotion of positive bystander behavior in cyberbullying among adolescents: examining the role of player experience and player behavior

info:eu-repo/semantics/nonPublishe

The Friendly ATTAC game: an intervention aimed at adolescent bystander behavior in cyberbullying

info:eu-repo/semantics/publishe

The Friendly ATTAC game: an intervention aimed at the promotion of positive bystander behavior in cyberbullying among adolescents: examining the role of player experience and player behavior

info:eu-repo/semantics/publishe