#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#
preLekára.sk / Odborné časopisy / PLOS Genetics / 2014 - 9

Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias

English version České info

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.

Vyšlo v časopise: Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004606
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004606

Souhrn

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.

Zdroje

1. SonnenJA, LarsonEB, CranePK, HaneuseS, LiG, et al. (2007) Pathological correlates of dementia in a longitudinal, population-based sample of aging. Ann Neurol 62 : 406–413.

2. SonnenJA, Santa CruzK, HemmyLS, WoltjerR, LeverenzJB, et al. (2011) Ecology of the aging human brain. Arch Neurol 68 : 1049–1056.

3. JackCRJr, KnopmanDS, JagustWJ, ShawLM, AisenPS, et al. (2010) Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 9 : 119–128.

4. HurdMD, MartorellP, DelavandeA, MullenKJ, LangaKM (2013) Monetary costs of dementia in the United States. N Engl J Med 368 : 1326–1334.

5. JunG, NajAC, BeechamGW, WangLS, BurosJ, et al. (2010) Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67 : 1473–1484.

6. NajAC, BeechamGW, MartinER, GallinsPJ, PowellEH, et al. (2010) Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities. PLoS Genet 6: e1001130.

7. HollingworthP, HaroldD, SimsR, GerrishA, LambertJC, et al. (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 43 : 429–435.

8. NajAC, JunG, BeechamGW, WangLS, VardarajanBN, et al. (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet 43 : 436–441.

9. JunG, VardarajanBN, BurosJ, YuCE, HawkMV, et al. (2012) Comprehensive search for Alzheimer disease susceptibility loci in the APOE region. Arch Neurol 69 : 1270–1279.

10. MiyashitaA, KoikeA, JunG, WangLS, TakahashiS, et al. (2013) SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians. PLoS One 8: e58618.

11. LambertJC, Ibrahim-VerbaasCA, HaroldD, NajAC, SimsR, et al. (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45 : 1452–1458.

12. CorderEH, SaundersAM, StrittmatterWJ, SchmechelDE, GaskellPC, et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261 : 921–923.

13. BenitezBA, JinSC, GuerreiroR, GrahamR, LordJ, et al. (2014) Missense variant in TREML2 protects against Alzheimer's disease. Neurobiol Aging 35 : 1510.e1519–1526.

14. CruchagaC, KarchCM, JinSC, BenitezBA, CaiY, et al. (2014) Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature 505 : 550–554.

15. ShulmanJM, ChenK, KeenanBT, ChibnikLB, FleisherA, et al. (2013) Genetic susceptibility for Alzheimer disease neuritic plaque pathology. JAMA Neurol 70 : 1150–1157.

16. TsuangD, LeverenzJB, LopezOL, HamiltonRL, BennettDA, et al. (2013) APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70 : 223–228.

17. WollmerMA, SleegersK, IngelssonM, ZekanowskiC, BrouwersN, et al. (2007) Association study of cholesterol-related genes in Alzheimer's disease. Neurogenetics 8 : 179–188.

18. EspinosaB, GuevaraJ, HernandezP, SlomiannyMC, GuzmanA, et al. (2003) Characterization of an O-glycosylated plaque-associated protein from Alzheimer disease brain. J Neuropathol Exp Neurol 62 : 34–41.

19. ArigaT, KobayashiK, HasegawaA, KisoM, IshidaH, et al. (2001) Characterization of high-affinity binding between gangliosides and amyloid beta-protein. Arch Biochem Biophys 388 : 225–230.

20. GraebertKS, PoppGM, KehleT, HerzogV (1995) Regulated O-glycosylation of the Alzheimer beta-A4 amyloid precursor protein in thyrocytes. Eur J Cell Biol 66 : 39–46.

21. MirraSS, HartMN, TerryRD (1993) Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists. Arch Pathol Lab Med 117 : 132–144.

22. BraakH, BraakE (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82 : 239–259.

23. HymanBT, TrojanowskiJQ (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 56 : 1095–1097.

24. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 : 559–575.

25. PriceAL, PattersonNJ, PlengeRM, WeinblattME, ShadickNA, et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 : 904–909.

26. MarchiniJ, HowieB, MyersS, McVeanG, DonnellyP (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39 : 906–913.

27. AbecasisGR, AutonA, BrooksLD, DePristoMA, DurbinRM, et al. (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491 : 56–65.

28. Venables W, Ripley D (2003) Modern Applied Statistics with S. New York: Springer. 497 p.

29. WillerCJ, LiY, AbecasisGR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26 : 2190–2191.

30. Hastie T, Pregibon D (1992) Generalized linear models. In: Chambers J, Hastie T, editors. Statistical Models in S. Pacific Grove, CA: Wadsworth & Brooks/Cole. pp. 195–246.

31. FriendlyM (2002) Corrgrams: Exploratory displays for correlation matrices. American Statistician 56 : 316–324.

Štítky
Genetika Reprodukčná medicína
Článek Translational Regulation of the Post-Translational Circadian Mechanism
Článek An Evolutionarily Conserved Role for the Aryl Hydrocarbon Receptor in the Regulation of Movement
Článek Eliminating Both Canonical and Short-Patch Mismatch Repair in Suggests a New Meiotic Recombination Model
Článek Requirement for Drosophila SNMP1 for Rapid Activation and Termination of Pheromone-Induced Activity
Článek Co-regulated Transcripts Associated to Cooperating eSNPs Define Bi-fan Motifs in Human Gene Networks
Článek Targeted H3R26 Deimination Specifically Facilitates Estrogen Receptor Binding by Modifying Nucleosome Structure
Článek Role for Circadian Clock Genes in Seasonal Timing: Testing the Bünning Hypothesis
Článek The Tandem Repeats Enabling Reversible Switching between the Two Phases of β-Lactamase Substrate Spectrum
Článek The Association of the Vanin-1 N131S Variant with Blood Pressure Is Mediated by Endoplasmic Reticulum-Associated Degradation and Loss of Function
Článek Identification of a Regulatory Variant That Binds FOXA1 and FOXA2 at the Type 2 Diabetes GWAS Locus
Článek Regulation of Flowering by the Histone Mark Readers MRG1/2 via Interaction with CONSTANS to Modulate Expression
Článek The Actomyosin Machinery Is Required for Retinal Lumen Formation
Článek Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus
Článek Hidden Diversity in Honey Bee Gut Symbionts Detected by Single-Cell Genomics
Článek Ribosome Rescue and Translation Termination at Non-Standard Stop Codons by ICT1 in Mammalian Mitochondria
Článek tRNA Modifying Enzymes, NSUN2 and METTL1, Determine Sensitivity to 5-Fluorouracil in HeLa Cells
Článek Causal Variation in Yeast Sporulation Tends to Reside in a Pathway Bottleneck
Článek Tissue-Specific RNA Expression Marks Distant-Acting Developmental Enhancers
Článek WC-1 Recruits SWI/SNF to Remodel and Initiate a Circadian Cycle
Článek Clonal Expansion of Early to Mid-Life Mitochondrial DNA Point Mutations Drives Mitochondrial Dysfunction during Human Ageing
Článek Methylation QTLs Are Associated with Coordinated Changes in Transcription Factor Binding, Histone Modifications, and Gene Expression Levels
Článek Differential Management of the Replication Terminus Regions of the Two Chromosomes during Cell Division
Článek Obesity-Linked Homologues and Establish Meal Frequency in
Článek Derlin-1 Regulates Mutant VCP-Linked Pathogenesis and Endoplasmic Reticulum Stress-Induced Apoptosis
Článek Stress-Induced Nuclear RNA Degradation Pathways Regulate Yeast Bromodomain Factor 2 to Promote Cell Survival
Článek The MAPK p38c Regulates Oxidative Stress and Lipid Homeostasis in the Intestine
Článek Widespread Genome Reorganization of an Obligate Virus Mutualist
Článek Trans-kingdom Cross-Talk: Small RNAs on the Move
Článek The Vip1 Inositol Polyphosphate Kinase Family Regulates Polarized Growth and Modulates the Microtubule Cytoskeleton in Fungi
Článek Myosin Vb Mediated Plasma Membrane Homeostasis Regulates Peridermal Cell Size and Maintains Tissue Homeostasis in the Zebrafish Epidermis
Článek GLD-4-Mediated Translational Activation Regulates the Size of the Proliferative Germ Cell Pool in the Adult Germ Line
Článek Genome Wide Association Studies Using a New Nonparametric Model Reveal the Genetic Architecture of 17 Agronomic Traits in an Enlarged Maize Association Panel
Článek Translational Regulation of the DOUBLETIME/CKIδ/ε Kinase by LARK Contributes to Circadian Period Modulation
Článek Positive Selection and Multiple Losses of the LINE-1-Derived Gene in Mammals Suggest a Dual Role in Genome Defense and Pluripotency
Článek Out of Balance: R-loops in Human Disease
Článek A Genetic Assay for Transcription Errors Reveals Multilayer Control of RNA Polymerase II Fidelity
Článek Altered Behavioral Performance and Live Imaging of Circuit-Specific Neural Deficiencies in a Zebrafish Model for Psychomotor Retardation
Článek Nipbl and Mediator Cooperatively Regulate Gene Expression to Control Limb Development
Článek Meta-analysis of Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments
Článek The Proprotein Convertase KPC-1/Furin Controls Branching and Self-avoidance of Sensory Dendrites in
Článek Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates
Článek Memory and Fitness Optimization of Bacteria under Fluctuating Environments
Článek Regulation of p53 and Rb Links the Alternative NF-κB Pathway to EZH2 Expression and Cell Senescence
Článek Interspecific Tests of Allelism Reveal the Evolutionary Timing and Pattern of Accumulation of Reproductive Isolation Mutations
Článek PRO40 Is a Scaffold Protein of the Cell Wall Integrity Pathway, Linking the MAP Kinase Module to the Upstream Activator Protein Kinase C
Článek Low Levels of p53 Protein and Chromatin Silencing of p53 Target Genes Repress Apoptosis in Endocycling Cells
Článek SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene
Článek RRP6L1 and RRP6L2 Function in Silencing Regulation of Antisense RNA Synthesis
Článek BMPs Regulate Gene Expression in the Dorsal Neuroectoderm of and Vertebrates by Distinct Mechanisms
Článek Unkempt Is Negatively Regulated by mTOR and Uncouples Neuronal Differentiation from Growth Control
Článek Atkinesin-13A Modulates Cell-Wall Synthesis and Cell Expansion in via the THESEUS1 Pathway
Článek Dopamine Signaling Leads to Loss of Polycomb Repression and Aberrant Gene Activation in Experimental Parkinsonism
Článek Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation
Článek Bipartite Recognition of DNA by TCF/Pangolin Is Remarkably Flexible and Contributes to Transcriptional Responsiveness and Tissue Specificity of Wingless Signaling
Článek The Olfactory Transcriptomes of Mice
Článek Muscular Dystrophy-Associated and Variants Disrupt Nuclear-Cytoskeletal Connections and Myonuclear Organization
Článek Interplay of dFOXO and Two ETS-Family Transcription Factors Determines Lifespan in
Článek Evidence for Widespread Positive and Negative Selection in Coding and Conserved Noncoding Regions of
Článek Rejuvenation of Meiotic Cohesion in Oocytes during Prophase I Is Required for Chiasma Maintenance and Accurate Chromosome Segregation
Článek Admixture in Latin America: Geographic Structure, Phenotypic Diversity and Self-Perception of Ancestry Based on 7,342 Individuals
Článek Local Effect of Enhancer of Zeste-Like Reveals Cooperation of Epigenetic and -Acting Determinants for Zygotic Genome Rearrangements
Článek Differential Responses to Wnt and PCP Disruption Predict Expression and Developmental Function of Conserved and Novel Genes in a Cnidarian
Článok vyšiel v časopise

PLOS Genetics

2014 Číslo 9
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

nový kurz
Autori: doc. MUDr. David Zemánek, Ph.D., MUDr. Anna Chaloupka, Ph.D.
Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#