当前位置： SCI文献检索 > PLoS Genetics期刊下所有文献 > Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology.

Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology.

Abstract：

:Late-Onset Alzheimer's disease (LOAD) is a common, complex genetic disorder well-known for its heterogeneous pathology. The genetic heterogeneity underlying common, complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, and two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10-8, rs1990620G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

Milind N,Preuss C,Haber A,Ananda G,Mukherjee S,John C,Shapley S,Logsdon BA,Crane PK,Carter GW

doi

10.1371/journal.pgen.1008775

subject

Has Abstract

pub_date

2020-06-03 00:00:00

pages

e1008775

issue

6

eissn

1553-7390

issn

1553-7404

pii

PGENETICS-D-19-01691

journal_volume

16

pub_type

杂志文章

相关文献

PLoS Genetics文献大全
  • Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabditis elegans larval development and immunity.

    abstract：:Endoplasmic reticulum (ER) stress activates the Unfolded Protein Response, a compensatory signaling response that is mediated by the IRE-1, PERK/PEK-1, and ATF-6 pathways in metazoans. Genetic studies have implicated roles for UPR signaling in animal development and disease, but the function of the UPR under physiolog...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1002391

    authors： Richardson CE,Kinkel S,Kim DH

    更新日期：2011-11-01 00:00:00

  • Parallel evolution of a type IV secretion system in radiating lineages of the host-restricted bacterial pathogen Bartonella.

    abstract：:Adaptive radiation is the rapid origination of multiple species from a single ancestor as the result of concurrent adaptation to disparate environments. This fundamental evolutionary process is considered to be responsible for the genesis of a great portion of the diversity of life. Bacteria have evolved enormous biol...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1001296

    authors： Engel P,Salzburger W,Liesch M,Chang CC,Maruyama S,Lanz C,Calteau A,Lajus A,Médigue C,Schuster SC,Dehio C

    更新日期：2011-02-10 00:00:00

  • Multiple loci are associated with white blood cell phenotypes.

    abstract：:White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from...

    journal_title：PLoS genetics

    pub_type： 杂志文章,meta分析

    doi：10.1371/journal.pgen.1002113

    authors： Nalls MA,Couper DJ,Tanaka T,van Rooij FJ,Chen MH,Smith AV,Toniolo D,Zakai NA,Yang Q,Greinacher A,Wood AR,Garcia M,Gasparini P,Liu Y,Lumley T,Folsom AR,Reiner AP,Gieger C,Lagou V,Felix JF,Völzke H,Gouskova NA,B

    更新日期：2011-06-01 00:00:00

  • A comprehensive map of mobile element insertion polymorphisms in humans.

    abstract：:As a consequence of the accumulation of insertion events over evolutionary time, mobile elements now comprise nearly half of the human genome. The Alu, L1, and SVA mobile element families are still duplicating, generating variation between individual genomes. Mobile element insertions (MEI) have been identified as cau...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1002236

    authors： Stewart C,Kural D,Strömberg MP,Walker JA,Konkel MK,Stütz AM,Urban AE,Grubert F,Lam HY,Lee WP,Busby M,Indap AR,Garrison E,Huff C,Xing J,Snyder MP,Jorde LB,Batzer MA,Korbel JO,Marth GT,1000 Genomes Project.

    更新日期：2011-08-01 00:00:00

  • Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA.

    abstract：:Human cancer is caused by the interplay of mutations in oncogenes and tumor suppressor genes and inherited variations in cancer susceptibility genes. While many of the tumor initiating mutations are well characterized, the effect of genetic background variation on disease onset and progression is less understood. We h...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1005236

    authors： Schmid T,Snoek LB,Fröhli E,van der Bent ML,Kammenga J,Hajnal A

    更新日期：2015-05-15 00:00:00

  • Genome-scale CRISPR screening for modifiers of cellular LDL uptake.

    abstract：:Hypercholesterolemia is a causal and modifiable risk factor for atherosclerotic cardiovascular disease. A critical pathway regulating cholesterol homeostasis involves the receptor-mediated endocytosis of low-density lipoproteins into hepatocytes, mediated by the LDL receptor. We applied genome-scale CRISPR screening t...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1009285

    authors： Emmer BT,Sherman EJ,Lascuna PJ,Graham SE,Willer CJ,Ginsburg D

    更新日期：2021-01-29 00:00:00

  • Budding Yeast Rif1 Controls Genome Integrity by Inhibiting rDNA Replication.

    abstract：:The Rif1 protein is a negative regulator of DNA replication initiation in eukaryotes. Here we show that budding yeast Rif1 inhibits DNA replication initiation at the rDNA locus. Absence of Rif1, or disruption of its interaction with PP1/Glc7 phosphatase, leads to more intensive rDNA replication. The effect of Rif1-Glc...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1006414

    authors： Shyian M,Mattarocci S,Albert B,Hafner L,Lezaja A,Costanzo M,Boone C,Shore D

    更新日期：2016-11-07 00:00:00

  • Stereotypic generation of axial tenocytes from bipartite sclerotome domains in zebrafish.

    abstract：:Development of a functional musculoskeletal system requires coordinated generation of muscles, bones, and tendons. However, how axial tendon cells (tenocytes) are generated during embryo development is still poorly understood. Here, we show that axial tenocytes arise from the sclerotome in zebrafish. In contrast to mo...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1007775

    authors： Ma RC,Jacobs CT,Sharma P,Kocha KM,Huang P

    更新日期：2018-11-02 00:00:00

  • The amidation step of diphthamide biosynthesis in yeast requires DPH6, a gene identified through mining the DPH1-DPH5 interaction network.

    abstract：:Diphthamide is a highly modified histidine residue in eukaryal translation elongation factor 2 (eEF2) that is the target for irreversible ADP ribosylation by diphtheria toxin (DT). In Saccharomyces cerevisiae, the initial steps of diphthamide biosynthesis are well characterized and require the DPH1-DPH5 genes. However...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1003334

    authors： Uthman S,Bär C,Scheidt V,Liu S,ten Have S,Giorgini F,Stark MJ,Schaffrath R

    更新日期：2013-01-01 00:00:00

  • The three faces of riboviral spontaneous mutation: spectrum, mode of genome replication, and mutation rate.

    abstract：:Riboviruses (RNA viruses without DNA replication intermediates) are the most abundant pathogens infecting animals and plants. Only a few riboviral infections can be controlled with antiviral drugs, mainly because of the rapid appearance of resistance mutations. Little reliable information is available concerning i) ki...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1002832

    authors： García-Villada L,Drake JW

    更新日期：2012-01-01 00:00:00

  • Sex reversal in zebrafish fancl mutants is caused by Tp53-mediated germ cell apoptosis.

    abstract：:The molecular genetic mechanisms of sex determination are not known for most vertebrates, including zebrafish. We identified a mutation in the zebrafish fancl gene that causes homozygous mutants to develop as fertile males due to female-to-male sex reversal. Fancl is a member of the Fanconi Anemia/BRCA DNA repair path...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1001034

    authors： Rodríguez-Marí A,Cañestro C,Bremiller RA,Nguyen-Johnson A,Asakawa K,Kawakami K,Postlethwait JH

    更新日期：2010-07-22 00:00:00

  • DNA damage as a consequence of NLR activation.

    abstract：:DNA damage observed during plant immune responses is reported to be an intrinsic component of plant immunity. However, other immune responses may suppress DNA damage to maintain host genome integrity. Here, we show that immunity-related DNA damage can be abrogated by preventing cell death triggered by Nucleotide-bindi...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1007235

    authors： Rodriguez E,Chevalier J,El Ghoul H,Voldum-Clausen K,Mundy J,Petersen M

    更新日期：2018-02-20 00:00:00

  • Tissue- and Time-Specific Expression of Otherwise Identical tRNA Genes.

    abstract：:Codon usage bias affects protein translation because tRNAs that recognize synonymous codons differ in their abundance. Although the current dogma states that tRNA expression is exclusively regulated by intrinsic control elements (A- and B-box sequences), we revealed, using a reporter that monitors the levels of indivi...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1006264

    authors： Sagi D,Rak R,Gingold H,Adir I,Maayan G,Dahan O,Broday L,Pilpel Y,Rechavi O

    更新日期：2016-08-25 00:00:00

  • Gene family evolution across 12 Drosophila genomes.

    abstract：:Comparison of whole genomes has revealed large and frequent changes in the size of gene families. These changes occur because of high rates of both gene gain (via duplication) and loss (via deletion or pseudogenization), as well as the evolution of entirely new genes. Here we use the genomes of 12 fully sequenced Dros...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.0030197

    authors： Hahn MW,Han MV,Han SG

    更新日期：2007-11-01 00:00:00

  • Ubiquitous polygenicity of human complex traits: genome-wide analysis of 49 traits in Koreans.

    abstract：:Recent studies in population of European ancestry have shown that 30% ~ 50% of heritability for human complex traits such as height and body mass index, and common diseases such as schizophrenia and rheumatoid arthritis, can be captured by common SNPs and that genetic variation attributed to chromosomes are in proport...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1003355

    authors： Yang J,Lee T,Kim J,Cho MC,Han BG,Lee JY,Lee HJ,Cho S,Kim H

    更新日期：2013-01-01 00:00:00

  • Dual function of perivascular fibroblasts in vascular stabilization in zebrafish.

    abstract：:Blood vessels are vital to sustain life in all vertebrates. While it is known that mural cells (pericytes and smooth muscle cells) regulate vascular integrity, the contribution of other cell types to vascular stabilization has been largely unexplored. Using zebrafish, we identified sclerotome-derived perivascular fibr...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1008800

    authors： Rajan AM,Ma RC,Kocha KM,Zhang DJ,Huang P

    更新日期：2020-10-26 00:00:00

  • Correction: Functional male accessory glands and fertility in Drosophila require novel ecdysone receptor.

    abstract：:[This corrects the article DOI: 10.1371/journal.pgen.1006788.]. ...

    journal_title：PLoS genetics

    pub_type： 已发布勘误

    doi：10.1371/journal.pgen.1006893

    authors： Sharma V,Pandey AK,Kumar A,Misra S,Gupta HPK,Gupta S,Singh A,Buehner NA,Ravi Ram K

    更新日期：2017-07-12 00:00:00

  • Hypomorphic mutation of the mouse Huntington's disease gene orthologue.

    abstract：:Rare individuals with inactivating mutations in the Huntington's disease gene (HTT) exhibit variable abnormalities that imply essential HTT roles during organ development. Here we report phenotypes produced when increasingly severe hypomorphic mutations in the murine HTT orthologue Htt, (HdhneoQ20, HdhneoQ50, HdhneoQ1...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1007765

    authors： Murthy V,Tebaldi T,Yoshida T,Erdin S,Calzonetti T,Vijayvargia R,Tripathi T,Kerschbamer E,Seong IS,Quattrone A,Talkowski ME,Gusella JF,Georgopoulos K,MacDonald ME,Biagioli M

    更新日期：2019-03-21 00:00:00

  • Cleavage factor I links transcription termination to DNA damage response and genome integrity maintenance in Saccharomyces cerevisiae.

    abstract：:During transcription, the nascent pre-mRNA undergoes a series of processing steps before being exported to the cytoplasm. The 3'-end processing machinery involves different proteins, this function being crucial to cell growth and viability in eukaryotes. Here, we found that the rna14-1, rna15-1, and hrp1-5 alleles of ...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1004203

    authors： Gaillard H,Aguilera A

    更新日期：2014-03-06 00:00:00

  • Octopamine neuromodulation regulates Gr32a-linked aggression and courtship pathways in Drosophila males.

    abstract：:Chemosensory pheromonal information regulates aggression and reproduction in many species, but how pheromonal signals are transduced to reliably produce behavior is not well understood. Here we demonstrate that the pheromonal signals detected by Gr32a-expressing chemosensory neurons to enhance male aggression are filt...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1004356

    authors： Andrews JC,Fernández MP,Yu Q,Leary GP,Leung AK,Kavanaugh MP,Kravitz EA,Certel SJ

    更新日期：2014-05-22 00:00:00

  • The transcriptomes of two heritable cell types illuminate the circuit governing their differentiation.

    abstract：:The differentiation of cells into distinct cell types, each of which is heritable for many generations, underlies many biological phenomena. White and opaque cells of the fungal pathogen Candida albicans are two such heritable cell types, each thought to be adapted to unique niches within their human host. To systemat...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1001070

    authors： Tuch BB,Mitrovich QM,Homann OR,Hernday AD,Monighetti CK,De La Vega FM,Johnson AD

    更新日期：2010-08-19 00:00:00

  • The euchromatic and heterochromatic landscapes are shaped by antagonizing effects of transcription on H2A.Z deposition.

    abstract：:A role for variant histone H2A.Z in gene expression is now well established but little is known about the mechanisms by which it operates. Using a combination of ChIP-chip, knockdown and expression profiling experiments, we show that upon gene induction, human H2A.Z associates with gene promoters and helps in recruiti...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1000687

    authors： Hardy S,Jacques PE,Gévry N,Forest A,Fortin ME,Laflamme L,Gaudreau L,Robert F

    更新日期：2009-10-01 00:00:00

  • Genomic variation predicts adaptive evolutionary responses better than population bottleneck history.

    abstract：:The relationship between population size, inbreeding, loss of genetic variation and evolutionary potential of fitness traits is still unresolved, and large-scale empirical studies testing theoretical expectations are surprisingly scarce. Here we present a highly replicated experimental evolution setup with 120 lines o...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1008205

    authors： Ørsted M,Hoffmann AA,Sverrisdóttir E,Nielsen KL,Kristensen TN

    更新日期：2019-06-12 00:00:00

  • The Spalt Transcription Factors Generate the Transcriptional Landscape of the Drosophila melanogaster Wing Pouch Central Region.

    abstract：:The Drosophila genes spalt major (salm) and spalt-related (salr) encode Zn-finger transcription factors regulated by the Decapentaplegic (Dpp) signalling pathway in the wing imaginal disc. The function of these genes is required for cell survival and proliferation in the central region of the wing disc, and also for v...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1005370

    authors： Organista MF,Martín M,de Celis JM,Barrio R,López-Varea A,Esteban N,Casado M,de Celis JF

    更新日期：2015-08-04 00:00:00

  • Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds.

    abstract：:Domestic dog breeds exhibit remarkable morphological variations that result from centuries of artificial selection and breeding. Identifying the genetic changes that contribute to these variations could provide critical insights into the molecular basis of tissue and organismal morphogenesis. Bulldogs, French Bulldogs...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1007850

    authors： Mansour TA,Lucot K,Konopelski SE,Dickinson PJ,Sturges BK,Vernau KL,Choi S,Stern JA,Thomasy SM,Döring S,Verstraete FJM,Johnson EG,York D,Rebhun RB,Ho HH,Brown CT,Bannasch DL

    更新日期：2018-12-06 00:00:00

  • Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B.

    abstract：:Multiple endocrine neoplasia type 2B (MEN2B) is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100-200 times greater than would be expected based on the genome average mutation fr...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1002420

    authors： Choi SK,Yoon SR,Calabrese P,Arnheim N

    更新日期：2012-01-01 00:00:00

  • CTCF genomic binding sites in Drosophila and the organisation of the bithorax complex.

    abstract：:Insulator or enhancer-blocking elements are proposed to play an important role in the regulation of transcription by preventing inappropriate enhancer/promoter interaction. The zinc-finger protein CTCF is well studied in vertebrates as an enhancer blocking factor, but Drosophila CTCF has only been characterised recent...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.0030112

    authors： Holohan EE,Kwong C,Adryan B,Bartkuhn M,Herold M,Renkawitz R,Russell S,White R

    更新日期：2007-07-01 00:00:00

  • Supramolecular assembly of the beta-catenin destruction complex and the effect of Wnt signaling on its localization, molecular size, and activity in vivo.

    abstract：:Wnt signaling provides a paradigm for cell-cell signals that regulate embryonic development and stem cell homeostasis and are inappropriately activated in cancers. The tumor suppressors APC and Axin form the core of the multiprotein destruction complex, which targets the Wnt-effector beta-catenin for phosphorylation, ...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1007339

    authors： Schaefer KN,Bonello TT,Zhang S,Williams CE,Roberts DM,McKay DJ,Peifer M

    更新日期：2018-04-11 00:00:00

  • The history of African gene flow into Southern Europeans, Levantines, and Jews.

    abstract：:Previous genetic studies have suggested a history of sub-Saharan African gene flow into some West Eurasian populations after the initial dispersal out of Africa that occurred at least 45,000 years ago. However, there has been no accurate characterization of the proportion of mixture, or of its date. We analyze genome-...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1001373

    authors： Moorjani P,Patterson N,Hirschhorn JN,Keinan A,Hao L,Atzmon G,Burns E,Ostrer H,Price AL,Reich D

    更新日期：2011-04-01 00:00:00

  • Rare genetic variation at transcription factor binding sites modulates local DNA methylation profiles.

    abstract：:Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Co...

    journal_title：PLoS genetics

    pub_type： 杂志文章

    doi：10.1371/journal.pgen.1009189

    authors： Martin-Trujillo A,Patel N,Richter F,Jadhav B,Garg P,Morton SU,McKean DM,DePalma SR,Goldmuntz E,Gruber D,Kim R,Newburger JW,Porter GA Jr,Giardini A,Bernstein D,Tristani-Firouzi M,Seidman JG,Seidman CE,Chung WK,Gelb B

    更新日期：2020-11-20 00:00:00