Meta-Analysis

. 2020 Jul 14;32(2):107908.

doi: 10.1016/j.celrep.2020.107908.

Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models

Ying-Wooi Wan¹, Rami Al-Ouran², Carl G Mangleburg¹, Thanneer M Perumal³, Tom V Lee⁴, Katherine Allison⁴, Vivek Swarup⁵, Cory C Funk⁶, Chris Gaiteri⁷, Mariet Allen⁸, Minghui Wang⁹, Sarah M Neuner¹⁰, Catherine C Kaczorowski¹⁰, Vivek M Philip¹⁰, Gareth R Howell¹⁰, Heidi Martini-Stoica¹¹, Hui Zheng¹², Hongkang Mei¹³, Xiaoyan Zhong¹³, Jungwoo Wren Kim¹⁴, Valina L Dawson¹⁵, Ted M Dawson¹⁶, Ping-Chieh Pao¹⁷, Li-Huei Tsai¹⁷, Jean-Vianney Haure-Mirande¹⁸, Michelle E Ehrlich¹⁹, Paramita Chakrabarty²⁰, Yona Levites²⁰, Xue Wang²¹, Eric B Dammer²², Gyan Srivastava²³, Sumit Mukherjee³, Solveig K Sieberts³, Larsson Omberg³, Kristen D Dang³, James A Eddy³, Phil Snyder³, Yooree Chae³, Sandeep Amberkar²⁴, Wenbin Wei²⁵, Winston Hide²⁶, Christoph Preuss¹⁰, Ayla Ergun²⁷, Phillip J Ebert²⁸, David C Airey²⁸, Sara Mostafavi²⁹, Lei Yu⁷, Hans-Ulrich Klein³⁰; Accelerating Medicines Partnership-Alzheimer’s Disease Consortium³¹; Gregory W Carter¹⁰, David A Collier³², Todd E Golde²⁰, Allan I Levey³³, David A Bennett⁷, Karol Estrada²⁷, T Matthew Townsend³⁴, Bin Zhang⁹, Eric Schadt⁹, Philip L De Jager³⁰, Nathan D Price⁶, Nilüfer Ertekin-Taner³⁵, Zhandong Liu³⁶, Joshua M Shulman³⁷, Lara M Mangravite³⁸, Benjamin A Logsdon³⁹

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
² Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
³ Sage Bionetworks, Seattle, WA 98121, USA.
⁴ Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
⁶ Institute for Systems Biology, Seattle, WA 98109, USA.
⁷ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁸ Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA.
⁹ Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
¹⁰ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
¹¹ Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
¹³ Neuroscience DPU, Shanghai R&D, GlaxoSmithKline, Shanghai, China.
¹⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin & Diana Helis Henry Medical Research Foundations, New Orleans, LA 70130, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁶ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin & Diana Helis Henry Medical Research Foundations, New Orleans, LA 70130, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁷ The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁸ Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
¹⁹ Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
²⁰ Evelyn F. and William L. McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA.
²¹ Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA; Mayo Clinic, Department of Health Sciences Research, Jacksonville, FL 32224, USA.
²² Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
²³ Data & Statistical Sciences, AbbVie, Cambridge, MA, USA.
²⁴ Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK; Molecular Oncology Lab, Cancer Research UK - Manchester Institute, The University of Manchester, Manchester, SK10 4TG, UK.
²⁵ Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK; Department of Biosciences, Durham University, Durham, DH1 3LE, UK.
²⁶ Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
²⁷ Translational Genome Sciences, Biogen, Cambridge, MA, USA.
²⁸ Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
²⁹ University of British Columbia, Vancouver, BC, Canada.
³⁰ Center for Translational & Computational Neuroimmunology, Department of Neurology and Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA; Cell Circuits Program, Broad Institute, Cambridge, MA 02142, USA.
³¹ Full consortium author list available at http://doi.org/10.7303/syn17114455.
³² Eli Lilly & Company, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK.
³³ Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
³⁴ Foundation Neuroscience Center, AbbVie, Cambridge, MA, USA.
³⁵ Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA; Mayo Clinic, Department of Neurology, Jacksonville, FL 32224, USA.
³⁶ Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: zhandonl@bcm.edu.
³⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: joshua.shulman@bcm.edu.
³⁸ Sage Bionetworks, Seattle, WA 98121, USA. Electronic address: lara.mangravite@sagebionetworks.org.
³⁹ Sage Bionetworks, Seattle, WA 98121, USA. Electronic address: ben.logsdon@sagebionetworks.org.

PMID: 32668255
PMCID: PMC7428328
DOI: 10.1016/j.celrep.2020.107908

Meta-Analysis

Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models

Ying-Wooi Wan et al. Cell Rep. 2020.

. 2020 Jul 14;32(2):107908.

doi: 10.1016/j.celrep.2020.107908.

Authors

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
² Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
³ Sage Bionetworks, Seattle, WA 98121, USA.
⁴ Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
⁶ Institute for Systems Biology, Seattle, WA 98109, USA.
⁷ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁸ Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA.
⁹ Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
¹⁰ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
¹¹ Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
¹³ Neuroscience DPU, Shanghai R&D, GlaxoSmithKline, Shanghai, China.
¹⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin & Diana Helis Henry Medical Research Foundations, New Orleans, LA 70130, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁶ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin & Diana Helis Henry Medical Research Foundations, New Orleans, LA 70130, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁷ The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁸ Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
¹⁹ Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
²⁰ Evelyn F. and William L. McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA.
²¹ Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA; Mayo Clinic, Department of Health Sciences Research, Jacksonville, FL 32224, USA.
²² Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
²³ Data & Statistical Sciences, AbbVie, Cambridge, MA, USA.
²⁴ Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK; Molecular Oncology Lab, Cancer Research UK - Manchester Institute, The University of Manchester, Manchester, SK10 4TG, UK.
²⁵ Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK; Department of Biosciences, Durham University, Durham, DH1 3LE, UK.
²⁶ Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
²⁷ Translational Genome Sciences, Biogen, Cambridge, MA, USA.
²⁸ Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
²⁹ University of British Columbia, Vancouver, BC, Canada.
³⁰ Center for Translational & Computational Neuroimmunology, Department of Neurology and Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA; Cell Circuits Program, Broad Institute, Cambridge, MA 02142, USA.
³¹ Full consortium author list available at http://doi.org/10.7303/syn17114455.
³² Eli Lilly & Company, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK.
³³ Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
³⁴ Foundation Neuroscience Center, AbbVie, Cambridge, MA, USA.
³⁵ Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA; Mayo Clinic, Department of Neurology, Jacksonville, FL 32224, USA.
³⁶ Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: zhandonl@bcm.edu.
³⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: joshua.shulman@bcm.edu.
³⁸ Sage Bionetworks, Seattle, WA 98121, USA. Electronic address: lara.mangravite@sagebionetworks.org.
³⁹ Sage Bionetworks, Seattle, WA 98121, USA. Electronic address: ben.logsdon@sagebionetworks.org.

PMID: 32668255
PMCID: PMC7428328
DOI: 10.1016/j.celrep.2020.107908

Abstract

We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.

Keywords: Alzheimer's disease; RNA-seq; aging; coexpression analysis; differential expression analysis; meta-analysis; mouse models; neuroinflammation; transcriptome.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

**Figure 1.. Human Consensus RNA-Seq Coexpression Modules**
(A) Gene set overlap (Fisher’s exact test p value) was examined among 30 AD-associated coexpression modules, highlighting five consensus clusters (A, B, C, D, and E). (B) Coexpression modules were evaluated using expression-weighted cell type enrichment analysis based on human single-cell RNA-seq. (C) Coexpression modules were examined for overlap (Fisher’s exact test) with curated AD gene sets from GeneCards, Panther, the Database of Genotypes and Phenotypes (dbGaP), IGAP, Online Mendelian Inheritance in Man (OMIM), Biocarta, Wikipathways, and the Kyoto Encyclopedia of Genes and Genomes (KEGG). We also evaluated overlap with coexpression modules derived from the constituent cohorts, including oligodendroglial modules identified by Mayo and MSSM, module 109 from ROSMAP, and an RNA-binding protein rich module from Emory. (D) Coexpression module enrichment for AD susceptibility gene candidates from GWAS, based on MAGMA. Consensus cluster B modules appear strongly enriched for AD risk loci.

**Figure 2.. Cross-Species Study Design and Data**
(A) Analytic design for examining overlaps between 30 Alzheimer’s disease (AD)-associated human coexpression modules and differentially expressed gene sets from 376 experimental comparisons in mouse models. (B) Ninety-six mouse studies were selected based on relevance to AD and other neurodegenerative disorders. Distribution of keywords is shown among all studies. RNA-seq was reprocessed using a standard pipeline. See Table S3 for details on all included mouse studies. (C) The differentially expressed gene sets represent mouse models of AD, Huntington’s disease (HD), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS), spinocerebellar ataxia 1 (SCA1), Rett syndrome (RETT), Parkinson’s disease (PD), Creutzfeldt-Jakob disease (CJD), neurofibromatosis (NF), or other neurodegenerative mechanisms. A t-distributed stochastic neighbor embedding (t-SNE) plot including all mouse differential expression signatures highlight both disease-specific and overlapping features among heterogeneous neurodegenerative models. See also Figure S3.

**Figure 3.. Overview of Human-Mouse Overlaps and Concordance**
Heatmaps show overlap (top) and concordance (bottom) among 30 human coexpression modules (rows) and 251 sets of differentially expressed genes (DEGs; columns) from mouse model comparisons. The average sample size is 8.4 (range 4–28 total samples). Mouse-human overlap significance, calculated using the hypergeometric test, is represented in grayscale (−log₁₀[p_adj]). Direction (red/blue) and extent of concordance (intensity) for gene expression changes are also indicated (bottom). The color bar at the top annotates all DEGs based on whether they derive from Alzheimer’s disease (AD) models (pink), other neurodegenerative models (purple), or other experimental manipulations potentially relevant to AD mechanisms (orange). The color barat left denotes cluster membership (A–E). Cluster E modules (brown, asterisk) show sparse overlap with AD mouse model DEGs. See Tables S4, S5, and S6 for details on all experimental comparisons and comprehensive results.

**Figure 4.. Human Coexpression Module Overlaps with AD Mouse Models**
(A) Heatmaps show overlap (top, hypergeometric test) and concordance (bottom) among human coexpression modules and sets of differentially expressed genes (DEGs) from Alzheimer’s disease (AD) mouse models. Mouse-human overlap significance, calculated using the hypergeometric test, is represented in grayscale (−log₁₀[p_adj]). The color bar at the top denotes APP (pink), MAPT (orange), or other (purple) model comparisons. The estimated pathologic burden (plaques/tangles and neuronal loss) in APP and MAPT models is also annotated in green. Cluster E modules (brown, asterisk) shows parse overlap with AD mouse models. Selected overlaps are denoted as follows: squares, APP models with oligodendrocyte-enriched module overlaps; cross-hatches, CRND8-APP models showing sustained activation of microglial modules from 6 months onward; arrowhead, transient activation of neuronal modules in TG4510-MAPT model preceding microglial module overlap; circles, co-activation of neuronal and microglial modules. See Tables S4 and S5 for details on all experimental comparisons, including sample sizes and genotypes, along with comprehensive results. See Figure S4 for duplicated panel including detailed model annotations. See Figure S6 for additional analysis of overlap specificity. (B) Representative overlaps of human modules with mouse DEGs. The hypergeometric test was applied to assess significance. Gene counts are noted in black, including for overlapping and non-overlapping regions. To assess concordance between human brains and mouse models, gene counts are shown, noting increased (red) or decreased expression (blue), including for the human coexpression module and the overlapping mouse gene set. M147 was derived from Srinivasan et al. (2016). (C) Mouse model overlaps highlight age- and sex-dependent changes. Increasing (red) or decreasing (blue) gene expression and magnitude of changes shown as overlap (%) between the mouse DEG set and module. Cell type module clusters are denoted by colors at panel bottom, as in (A). (D) Enrichment of human sex-specific DEGs from random-effects meta-analysis among coexpression modules. Consensus cluster C shows downregulation in AD among females.

**Figure 5.. Overlaps with Other Mouse Models**
(A) Heatmaps show overlap among human coexpression modules and sets of differentially expressed genes (DEGs) from mouse models, including pure aging, neurodegenerative disorders, and other experimental manipulations. HD, Huntington’s disease; FTD-ALS, frontotemporal dementia-amyotrophic lateral sclerosis; SCA1, spinocerebellar ataxia 1; CJD, Creutzfeldt-Jakob disease. Mouse-human overlap significance, calculated using the hypergeometric test, is represented in grayscale (−log₁₀[p_adj]). Overlaps between HD model expression signatures (Langfelder et al., 2016) and neuronal gene-enriched human coexpression modules recapitulate polyglutamine length (M100, Q92 versus M94, Q175) and brain region dependence (M100/M94, striatum versus M72/M81, cortex). Other manipulations generate signatures similar to AD models, including *PTCH1* knockout (M183) (Ung et al., 2018), *nmf205* (M182) (Ishimura et al., 2016), and *neuroserpin* mutant (M205) (Guadagno et al., 2017). Modules poorly enriched for cell type signatures (asterisk, right) show selected overlaps with FTD-ALS models (M28, M43; Ibrahim et al., 2013, and Lagier-Tourenne et al., 2013, respectively) and other, unexpected genetic manipulations (M158, M111, M54, and M156; Vied et al., 2016, Maze et al., 2015, Narayanan et al., 2014, and Holmes et al., 2016, respectively). See Tables S5 and S6 for comprehensive results, including sample sizes for all comparisons. See Figure S5 for comprehensive heatmaps representing overlaps with HD, FTD-ALS, SCA1, and aging models. (B) Representative overlaps of human modules with mouse DEGs, as in Figure 4B. The hypergeometric test was applied to assess significance.

See this image and copyright information in PMC

References

1. Adalbert R, Nogradi A, Babetto E, Janeckova L, Walker SA, Kerschensteiner M, Misgeld T, and Coleman MP (2009). Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies. Brain 132, 402–416. - PubMed
1. Adamcsek B, Palla G, Farkas IJ, Derenyi I, and Vicsek T (2006). CFinder: locating cliques and overlapping modules in biological networks. Bioinformatics 22, 1021–1023. - PubMed
1. Ahn Y-Y, Bagrow JP, and Lehmann S (2010). Link communities reveal multiscale complexity in networks. Nature 466, 761–764. - PubMed
1. Allen M, Carrasquillo MM, Funk C, Heavner BD, Zou F, Younkin CS, Burgess JD, Chai H-S, Crook J, Eddy JA, et al. (2016). Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases. Sci. Data 3, 160089. - PMC - PubMed
1. Allen M, Wang X, Burgess JD, Watzlawik J, Serie DJ, Younkin CS, Nguyen T, Malphrus KG, Lincoln S, Carrasquillo MM, et al. (2018). Conserved brain myelination networks are altered in Alzheimer’s and other neurodegenerative diseases. Alzheimers Dement. 14, 352–366. - PMC - PubMed

Publication types

Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models

Affiliations

Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical