Genome-wide association for major depression through age at onset stratification

BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer’s disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11–1.21, p = 5.2 × 10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder

Surface Damage Evaluation and Computational Modelling of Clinically Failed Knee Liners

Five retrieved knee liners made of cross-linked, ultra-high molecular weight polyethylene were investigated. Each liner was examined by five investigators and in vivo damage was evaluated using four methods (Wasielewski, Brandt, Lombardi, and Hood). Both optical and confocal microscopy techniques were used to quantify damage modes. Oxidation index, crystallinity and hardness parameters were calculated for material characterization. Gait profiles of two subjects (one male and one female) for three different activities were considered in finite element analysis (FEA) simulations. The main hypotheses of this study were that 1) the wear tracks on the liners may be represented by maximum von Mises stress areas, 2) a single composite index may be used to represent 10 different damage modes. Significant reduction in tensile strength was observed with an average value of 27.7 MPa at 50KGy due to oxidation in all the liners. Correlations were made between FEA results and surface evaluation results. Gait analysis of the liners showed males typically have a higher stress level in vivo than females, leading to increased wear. Attempts were made to relate the damage patterns on the liners with the stress development and the damage evaluation methods and our computational simulation validates the methods that we used. Higher stress areas were compared against the surface evaluation results, showing those regions experiencing the high stress also had a high damage index. Even though the liners were mechanically intact, they failed clinically and more likely due to abrasive wear (due to third-body wear particles). [ABSTRACT FROM AUTHOR] Copyright of Computer Methods in Biomechanics & Biomedical Engineering: Imaging & Visualisation is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder\u27s express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.

Surface Damage Evaluation and Computational Modelling of Clinically Failed Knee Liners

Five retrieved knee liners made of cross-linked, ultra-high molecular weight polyethylene were investigated. Each liner was examined by five investigators and in vivo damage was evaluated using four methods (Wasielewski, Brandt, Lombardi, and Hood). Both optical and confocal microscopy techniques were used to quantify damage modes. Oxidation index, crystallinity and hardness parameters were calculated for material characterization. Gait profiles of two subjects (one male and one female) for three different activities were considered in finite element analysis (FEA) simulations. The main hypotheses of this study were that 1) the wear tracks on the liners may be represented by maximum von Mises stress areas, 2) a single composite index may be used to represent 10 different damage modes. Significant reduction in tensile strength was observed with an average value of 27.7 MPa at 50KGy due to oxidation in all the liners. Correlations were made between FEA results and surface evaluation results. Gait analysis of the liners showed males typically have a higher stress level in vivo than females, leading to increased wear. Attempts were made to relate the damage patterns on the liners with the stress development and the damage evaluation methods and our computational simulation validates the methods that we used. Higher stress areas were compared against the surface evaluation results, showing those regions experiencing the high stress also had a high damage index. Even though the liners were mechanically intact, they failed clinically and more likely due to abrasive wear (due to third-body wear particles). [ABSTRACT FROM AUTHOR] Copyright of Computer Methods in Biomechanics & Biomedical Engineering: Imaging & Visualisation is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder\u27s express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.

Improving the Probability of Success of Repeated Genetic Algorithm on Affine Object Location Problem

Les textes publiés dans la série des rapports de recherche HEC n’engagent que la responsabilité de leurs auteurs. La publication de ces rapports de recherche bénéficie d’une subvention du Fonds québécois de la recherche sur la nature et les technologies

Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology

Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.status: publishe

Genetic overlap between Alzheimer's Disease and Parkinson's Disease at the MAPT locus

We investigated the genetic overlap between Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10−7). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer’s neurodegeneration

Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10 -7). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration