Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Stratégies anti-aspergillaires (revue de la littérature et étude à propos de 16 cas d'aspergillose invasive dans une unité d'hémato-oncologie)

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Bouvard et Pécuchet : la fiction des savoirs

Dans Bouvard et Pécuchet, Flaubert déconstruit discours et représentations. Il élabore une oeuvre paradoxale : la critique devient une puissance d’invention et de mise en forme, une force qui s’allie curieusement à l’imaginaire. Ainsi le roman se libère-t-il de la « colle » romanesque - sentiments, amour, aventures, actions - qu’un Huysmans ne tardera pas à critiquer dans Là-Bas. Pourtant cette oeuvre préserve encore une part de narrativité. Écrire un roman dans lequel les événements majeurs sont des controverses, faire rire avec des théories, tel est le pari difficile de Flaubert qui réoriente le roman dans une voie bien peu balzacienne. Il n y a que des manières de voir, écrit-il en pleine période naturaliste. Avec Bouvard et Pécuchet il invente une forme nouvelle de roman philosophique qui met en question le rapport de la représentation au réel. Ce numéro aborde la fiction des savoirs à partir du texte, des manuscrits, des scénarios et des notes documentaires. Ses auteurs s’interrogent sur l’objectif de l’oeuvre, sur la puissance critique de la fiction, sur la portée philosophique d’un roman qui n’épargne pas les philosophies, sur la valeur cognitive de la fiction, sur la transformation du genre romanesque et de la conception du personnage. De la quête balzacienne de l’absolu à la revue des idées modernes, le genre romanesque connait une véritable révolution. Du réel à la bibliothèque, le centre de gravité se déplace. Roman philosophique confronté à la profusion des discours et des représentations, Bouvard et Pécuchet invente une archéologie de la modernité en farce

Dehydrin-like proteins in the necrotrophic fungus Alternaria brassicicola have a role in plant pathogenesis and stress response.

In this study, the roles of fungal dehydrin-like proteins in pathogenicity and protection against environmental stresses were investigated in the necrotrophic seed-borne fungus Alternaria brassicicola. Three proteins (called AbDhn1, AbDhn2 and AbDhn3), harbouring the asparagine-proline-arginine (DPR) signature pattern and sharing the characteristic features of fungal dehydrin-like proteins, were identified in the A. brassicicola genome. The expression of these genes was induced in response to various stresses and found to be regulated by the AbHog1 mitogen-activated protein kinase (MAPK) pathway. A knock-out approach showed that dehydrin-like proteins have an impact mainly on oxidative stress tolerance and on conidial survival upon exposure to high and freezing temperatures. The subcellular localization revealed that AbDhn1 and AbDhn2 were associated with peroxisomes, which is consistent with a possible perturbation of protective mechanisms to counteract oxidative stress and maintain the redox balance in AbDhn mutants. Finally, we show that the double deletion mutant ΔΔabdhn1-abdhn2 was highly compromised in its pathogenicity. By comparison to the wild-type, this mutant exhibited lower aggressiveness on B. oleracea leaves and a reduced capacity to be transmitted to Arabidopsis seeds via siliques. The double mutant was also affected with respect to conidiation, another crucial step in the epidemiology of the disease

Susceptibility of AbDhn-deficient mutants to temperature stress.

<p>Calibrated water suspensions of conidia from the wild-type (WT) strain <i>Abra43</i> and AbDhn-deficient mutants were left for 10 h at various temperatures (−20°C, +4°C, +20°C, +40°C). Conidia were then used to inoculate microplate wells and nephelometric growth curves were established over a 33 h period. ΔLag time was calculated as the difference between the lag time at the tested temperature and the lag time at 20°C and was used as a parameter to estimate the effect of the treatment on spore viability. Error bars indicate standard deviations and asterisks indicate values that are significantly (<i>P</i><0.01) higher than that of the wild-type. Each genotype was analysed in triplicate and the experiments were repeated twice times per growth condition.</p

Subcellular localization of the AbDhn1-GFP fusion protein.

<p>Double-labelled strains expressing AbDhn1<i>-</i>GFP and DsRed-SKL were exposed to 350 mM NaCl for 2 h. Co-localization analyses in conidia (A) and hyphae (B) were examined using confocal microscopy. Bars = 10 µm.</p

Alternative splicing of the <i>AbDhn2</i> transcript.

<p>A: Electrophoresis gel of PCR products obtained after amplification of the <i>AbDhn2</i> coding sequence using genomic DNA (lane g) or first-strand cDNA (lane RT) as template; Lane L: DNA ladder. B: Schematic representation of the splicing events leading to α and β forms of mature transcripts. Exons are indicated as black or hatched boxes.</p