11 research outputs found
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 Δ4 allele
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 Δ4 allele
An eprinomectin extended-release injection formulation providing nematode control in cattle for up to 150 days
Nematode burdens of pastured cattle treated once at turnout with eprinomectin extended-release injection
Persistent efficacy and production benefits following use of extended-release injectable eprinomectin in grazing beef cattle under field conditions
Supplementary Material for: Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimerâs Disease Sequencing Project
<b><i>Background/Aims:</i></b> The Alzheimerâs Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimerâs disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. <b><i>Methods:</i></b> We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as âpathogenicâ in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. <b><i>Results/Conclusions:</i></b> Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within <i>ARSA</i>, <i>CSF1R</i>, and <i>GRN</i> were observed, and candidate variants in <i>GRN</i> and <i>CHMP2B</i> were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in <i>TREM2</i>, <i>APOE</i>, <i>ARSA</i>, <i>CSF1R</i>, <i>PSEN1</i>, and <i>MAPT</i> and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP
Correction: Whole exome sequencing study identifies novel rare and common Alzheimerâs-Associated variants involved in immune response and transcriptional regulation (Molecular Psychiatry, (2018), 10.1038/s41380-018-0112-7)
Following publication, the authors noticed that âLaura Cantwellâ, âOtto Valladaresâ, and âLi-San Wangâ were inadvertently omitted from the author list. These authors have now been added to the author list in 21st, 77th, and 79th position, respectively. This has been corrected in both the PDF and HTML versions of the article
Convergent genetic and expression data implicate immunity in Alzheimer's disease.
To access publisher's full text version of this article click on the hyperlink at the bottom of the pageLate-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (PÂ =Â 3.27Â ĂÂ 10(-12) after multiple testing correction for pathways), regulation of endocytosis (PÂ =Â 1.31Â ĂÂ 10(-11)), cholesterol transport (PÂ =Â 2.96Â ĂÂ 10(-9)), and proteasome-ubiquitin activity (PÂ =Â 1.34Â ĂÂ 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05).The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.Wellcome Trust
Medical Research Council
Alzheimer's Research UK
Welsh Assembly Government
National Institutes of Health, National Institute on Aging (NIH-NIA)
Erasmus Medical Center
Erasmus University
French National Foundation on Alzheimer's Disease and Related Disorders
Centre National de Genotypage
Institut Pasteur de Lille
Inserm
FRC (Fondation pour la Recherche sur le Cerveau)
Rotary
LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease)
Alzheimer's Associatio
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 Δ4 allele. © 2022. The Author(s)