41 results on '"McCabe, Cristin"'
Search Results
2. Correction of age-associated defects in dendritic cells enables CD4+ T cells to eradicate tumors
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Zhivaki, Dania, Kennedy, Stephanie N., Park, Josh, Boriello, Francesco, Devant, Pascal, Cao, Anh, Bahleda, Kristin M., Murphy, Shane, McCabe, Cristin, Evavold, Charles L., Chapman, Kate L., Zanoni, Ivan, Ashenberg, Orr, Xavier, Ramnik J., and Kagan, Jonathan C.
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- 2024
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3. Multicellular communities are perturbed in the aging human brain and Alzheimer’s disease
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Cain, Anael, Taga, Mariko, McCabe, Cristin, Green, Gilad S., Hekselman, Idan, White, Charles C., Lee, Dylan I., Gaur, Pallavi, Rozenblatt-Rosen, Orit, Zhang, Feng, Yeger-Lotem, Esti, Bennett, David A., Yang, Hyun-Sik, Regev, Aviv, Menon, Vilas, Habib, Naomi, and De Jager, Philip L.
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- 2023
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4. The effect of background noise and its removal on the analysis of single-cell expression data
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Janssen, Philipp, Kliesmete, Zane, Vieth, Beate, Adiconis, Xian, Simmons, Sean, Marshall, Jamie, McCabe, Cristin, Heyn, Holger, Levin, Joshua Z., Enard, Wolfgang, and Hellmann, Ines
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- 2023
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5. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility
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Patsopoulos, Nikolaos A, Baranzini, Sergio E, Santaniello, Adam, Shoostari, Parisa, Cotsapas, Chris, Wong, Garrett, Beecham, Ashley H, James, Tojo, Replogle, Joseph, Vlachos, Ioannis S, McCabe, Cristin, Pers, Tune H, Brandes, Aaron, White, Charles, Keenan, Brendan, Cimpean, Maria, Winn, Phoebe, Panteliadis, Ioannis-Pavlos, Robbins, Allison, Andlauer, Till FM, Zarzycki, Onigiusz, Dubois, Bénédicte, Goris, An, Søndergaard, Helle Bach, Sellebjerg, Finn, Sorensen, Per Soelberg, Ullum, Henrik, Thørner, Lise Wegner, Saarela, Janna, Cournu-Rebeix, Isabelle, Damotte, Vincent, Fontaine, Bertrand, Guillot-Noel, Lena, Lathrop, Mark, Vukusic, Sandra, Berthele, Achim, Pongratz, Viola, Buck, Dorothea, Gasperi, Christiane, Graetz, Christiane, Grummel, Verena, Hemmer, Bernhard, Hoshi, Muni, Knier, Benjamin, Korn, Thomas, Lill, Christina M, Luessi, Felix, Mühlau, Mark, Zipp, Frauke, Dardiotis, Efthimios, Agliardi, Cristina, Amoroso, Antonio, Barizzone, Nadia, Benedetti, Maria D, Bernardinelli, Luisa, Cavalla, Paola, Clarelli, Ferdinando, Comi, Giancarlo, Cusi, Daniele, Esposito, Federica, Ferrè, Laura, Galimberti, Daniela, Guaschino, Clara, Leone, Maurizio A, Martinelli, Vittorio, Moiola, Lucia, Salvetti, Marco, Sorosina, Melissa, Vecchio, Domizia, Zauli, Andrea, Santoro, Silvia, Mancini, Nicasio, Zuccalà, Miriam, Mescheriakova, Julia, van Duijn, Cornelia, Bos, Steffan D, Celius, Elisabeth G, Spurkland, Anne, Comabella, Manuel, Montalban, Xavier, Alfredsson, Lars, Bomfim, Izaura L, Gomez-Cabrero, David, Hillert, Jan, Jagodic, Maja, Lindén, Magdalena, Piehl, Fredrik, Jelčić, Ilijas, Martin, Roland, Sospedra, Mirela, Baker, Amie, Ban, Maria, Hawkins, Clive, Hysi, Pirro, Kalra, Seema, Karpe, Fredrik, Khadake, Jyoti, Lachance, Genevieve, Molyneux, Paul, and Neville, Matthew
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Neurosciences ,Brain Disorders ,Multiple Sclerosis ,Human Genome ,Autoimmune Disease ,Clinical Research ,Genetics ,Neurodegenerative ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Neurological ,Case-Control Studies ,Cell Cycle Proteins ,Chromosome Mapping ,Chromosomes ,Human ,X ,GTPase-Activating Proteins ,Gene Frequency ,Genetic Loci ,Genome-Wide Association Study ,Genomics ,Humans ,Inheritance Patterns ,Major Histocompatibility Complex ,Microglia ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,RNA-Seq ,Transcriptome ,International Multiple Sclerosis Genetics Consortium ,General Science & Technology - Abstract
We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.
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- 2019
6. Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection
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Ye, Chun Jimmie, Chen, Jenny, Villani, Alexandra-Chloé, Gate, Rachel E, Subramaniam, Meena, Bhangale, Tushar, Lee, Mark N, Raj, Towfique, Raychowdhury, Raktima, Li, Weibo, Rogel, Noga, Simmons, Sean, Imboywa, Selina H, Chipendo, Portia I, McCabe, Cristin, Lee, Michelle H, Frohlich, Irene Y, Stranger, Barbara E, De Jager, Philip L, Regev, Aviv, Behrens, Tim, and Hacohen, Nir
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Biological Sciences ,Genetics ,Infectious Diseases ,Biotechnology ,Human Genome ,Pneumonia & Influenza ,Influenza ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Adolescent ,Adult ,Alternative Splicing ,Aminopeptidases ,Chromosome Mapping ,Computational Biology ,Dendritic Cells ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Gene Ontology ,Genetic Predisposition to Disease ,Genetic Testing ,Genetic Variation ,Host-Pathogen Interactions ,Humans ,Influenza A virus ,Influenza ,Human ,Interferon Type I ,Male ,Middle Aged ,Models ,Biological ,Molecular Sequence Annotation ,Monocytes ,Quantitative Trait Loci ,Transcriptome ,Young Adult ,Medical and Health Sciences ,Bioinformatics - Abstract
While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs (eQTLs) for the same gene. Compared with eQTLs, isoQTLs are enriched for splice sites and untranslated regions, but depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs explain a significant proportion of the disease heritability attributed to common genetic variants. At the ERAP2 locus, we shed light on the function of the gene and how two frequent, highly differentiated haplotypes with intermediate frequencies could be maintained by balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with low ERAP2 expression caused by nonsense-mediated decay, while the minor haplotype, known to increase Crohn's disease risk, is associated with high ERAP2 expression. In response to influenza infection, we found two uncharacterized isoforms expressed from the major haplotype, likely the result of multiple perfectly linked variants affecting the transcription and splicing at the locus. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in innate immune responses and, in the case of ERAP2, may confer a historical fitness advantage in response to virus.
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- 2018
7. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets
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Delorey, Toni M., Ziegler, Carly G. K., Heimberg, Graham, Normand, Rachelly, Yang, Yiming, Segerstolpe, Åsa, Abbondanza, Domenic, Fleming, Stephen J., Subramanian, Ayshwarya, Montoro, Daniel T., Jagadeesh, Karthik A., Dey, Kushal K., Sen, Pritha, Slyper, Michal, Pita-Juárez, Yered H., Phillips, Devan, Biermann, Jana, Bloom-Ackermann, Zohar, Barkas, Nikolaos, Ganna, Andrea, Gomez, James, Melms, Johannes C., Katsyv, Igor, Normandin, Erica, Naderi, Pourya, Popov, Yury V., Raju, Siddharth S., Niezen, Sebastian, Tsai, Linus T.-Y., Siddle, Katherine J., Sud, Malika, Tran, Victoria M., Vellarikkal, Shamsudheen K., Wang, Yiping, Amir-Zilberstein, Liat, Atri, Deepak S., Beechem, Joseph, Brook, Olga R., Chen, Jonathan, Divakar, Prajan, Dorceus, Phylicia, Engreitz, Jesse M., Essene, Adam, Fitzgerald, Donna M., Fropf, Robin, Gazal, Steven, Gould, Joshua, Grzyb, John, Harvey, Tyler, Hecht, Jonathan, Hether, Tyler, Jané-Valbuena, Judit, Leney-Greene, Michael, Ma, Hui, McCabe, Cristin, McLoughlin, Daniel E., Miller, Eric M., Muus, Christoph, Niemi, Mari, Padera, Robert, Pan, Liuliu, Pant, Deepti, Pe’er, Carmel, Pfiffner-Borges, Jenna, Pinto, Christopher J., Plaisted, Jacob, Reeves, Jason, Ross, Marty, Rudy, Melissa, Rueckert, Erroll H., Siciliano, Michelle, Sturm, Alexander, Todres, Ellen, Waghray, Avinash, Warren, Sarah, Zhang, Shuting, Zollinger, Daniel R., Cosimi, Lisa, Gupta, Rajat M., Hacohen, Nir, Hibshoosh, Hanina, Hide, Winston, Price, Alkes L., Rajagopal, Jayaraj, Tata, Purushothama Rao, Riedel, Stefan, Szabo, Gyongyi, Tickle, Timothy L., Ellinor, Patrick T., Hung, Deborah, Sabeti, Pardis C., Novak, Richard, Rogers, Robert, Ingber, Donald E., Jiang, Z. Gordon, Juric, Dejan, Babadi, Mehrtash, Farhi, Samouil L., Izar, Benjamin, Stone, James R., Vlachos, Ioannis S., Solomon, Isaac H., Ashenberg, Orr, Porter, Caroline B. M., Li, Bo, Shalek, Alex K., Villani, Alexandra-Chloé, Rozenblatt-Rosen, Orit, and Regev, Aviv
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- 2021
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8. Atlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue
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Ma, Yiyi, Dammer, Eric B., Felsky, Daniel, Duong, Duc M., Klein, Hans-Ulrich, White, Charles C., Zhou, Maotian, Logsdon, Benjamin A., McCabe, Cristin, Xu, Jishu, Wang, Minghui, Wingo, Thomas S., Lah, James J., Zhang, Bin, Schneider, Julie, Allen, Mariet, Wang, Xue, Ertekin-Taner, Nilüfer, Seyfried, Nicholas T., Levey, Allan I., Bennett, David A., and De Jager, Philip L.
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- 2021
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9. Disease-associated astrocytes in Alzheimer’s disease and aging
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Habib, Naomi, McCabe, Cristin, Medina, Sedi, Varshavsky, Miriam, Kitsberg, Daniel, Dvir-Szternfeld, Raz, Green, Gilad, Dionne, Danielle, Nguyen, Lan, Marshall, Jamie L., Chen, Fei, Zhang, Feng, Kaplan, Tommy, Regev, Aviv, and Schwartz, Michal
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- 2020
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10. Intersection of population variation and autoimmunity genetics in human T cell activation
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Ye, Chun Jimmie, Feng, Ting, Kwon, Ho-Keun, Raj, Towfique, Wilson, Michael T, Asinovski, Natasha, McCabe, Cristin, Lee, Michelle H, Frohlich, Irene, Paik, Hyun-il, Zaitlen, Noah, Hacohen, Nir, Stranger, Barbara, De Jager, Philip, Mathis, Diane, Regev, Aviv, and Benoist, Christophe
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Human Genome ,Genetics ,Clinical Research ,Biotechnology ,Autoimmune Disease ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Asians ,Autoimmunity ,Blacks ,CD4-Positive T-Lymphocytes ,Cytokines ,Gene Expression Regulation ,Genetic Variation ,Genome-Wide Association Study ,Humans ,Lymphocyte Activation ,Multigene Family ,Quantitative Trait Loci ,Th17 Cells ,Whites ,Asian People ,White People ,Black People ,General Science & Technology - Abstract
T lymphocyte activation by antigen conditions adaptive immune responses and immunopathologies, but we know little about its variation in humans and its genetic or environmental roots. We analyzed gene expression in CD4(+) T cells during unbiased activation or in T helper 17 (T(H)17) conditions from 348 healthy participants representing European, Asian, and African ancestries. We observed interindividual variability, most marked for cytokine transcripts, with clear biases on the basis of ancestry, and following patterns more complex than simple T(H)1/2/17 partitions. We identified 39 genetic loci specifically associated in cis with activated gene expression. We further fine-mapped and validated a single-base variant that modulates YY1 binding and the activity of an enhancer element controlling the autoimmune-associated IL2RA gene, affecting its activity in activated but not regulatory T cells. Thus, interindividual variability affects the fundamental immunologic process of T helper activation, with important connections to autoimmune disease.
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- 2014
11. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci
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De Jager, Philip L, Srivastava, Gyan, Lunnon, Katie, Burgess, Jeremy, Schalkwyk, Leonard C, Yu, Lei, Eaton, Matthew L, Keenan, Brendan T, Ernst, Jason, McCabe, Cristin, Tang, Anna, Raj, Towfique, Replogle, Joseph, Brodeur, Wendy, Gabriel, Stacey, Chai, High S, Younkin, Curtis, Younkin, Steven G, Zou, Fanggeng, Szyf, Moshe, Epstein, Charles B, Schneider, Julie A, Bernstein, Bradley E, Meissner, Alex, Ertekin-Taner, Nilufer, Chibnik, Lori B, Kellis, Manolis, Mill, Jonathan, and Bennett, David A
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Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Alzheimer's Disease ,Human Genome ,Genetics ,Dementia ,Neurodegenerative ,Acquired Cognitive Impairment ,Aging ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adaptor Proteins ,Signal Transducing ,Aged ,Aged ,80 and over ,Alzheimer Disease ,Amyloidosis ,Ankyrins ,Brain ,Carrier Proteins ,CpG Islands ,DNA Methylation ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Intracellular Signaling Peptides and Proteins ,Male ,Middle Aged ,Nuclear Proteins ,Protein Interaction Maps ,Tumor Suppressor Proteins ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.
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- 2014
12. Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes
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Raj, Towfique, Rothamel, Katie, Mostafavi, Sara, Ye, Chun, Lee, Mark N, Replogle, Joseph M, Feng, Ting, Lee, Michelle, Asinovski, Natasha, Frohlich, Irene, Imboywa, Selina, Von Korff, Alina, Okada, Yukinori, Patsopoulos, Nikolaos A, Davis, Scott, McCabe, Cristin, Paik, Hyun-il, Srivastava, Gyan P, Raychaudhuri, Soumya, Hafler, David A, Koller, Daphne, Regev, Aviv, Hacohen, Nir, Mathis, Diane, Benoist, Christophe, Stranger, Barbara E, and De Jager, Philip L
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Aging ,Neurodegenerative ,Genetics ,Dementia ,Acquired Cognitive Impairment ,Clinical Research ,Brain Disorders ,Human Genome ,Prevention ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Adaptive Immunity ,Alleles ,Alzheimer Disease ,Autoimmune Diseases ,Autoimmunity ,CD4-Positive T-Lymphocytes ,Ethnicity ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Immunity ,Innate ,Monocytes ,Multiple Sclerosis ,Neurodegenerative Diseases ,Parkinson Disease ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,Rheumatic Fever ,Transcriptome ,General Science & Technology - Abstract
To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4(+) T cells and monocytes, representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer's and Parkinson's disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.
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- 2014
13. Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells
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Lee, Mark N, Ye, Chun, Villani, Alexandra-Chloé, Raj, Towfique, Li, Weibo, Eisenhaure, Thomas M, Imboywa, Selina H, Chipendo, Portia I, Ran, F Ann, Slowikowski, Kamil, Ward, Lucas D, Raddassi, Khadir, McCabe, Cristin, Lee, Michelle H, Frohlich, Irene Y, Hafler, David A, Kellis, Manolis, Raychaudhuri, Soumya, Zhang, Feng, Stranger, Barbara E, Benoist, Christophe O, De Jager, Philip L, Regev, Aviv, and Hacohen, Nir
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Infectious Diseases ,Influenza ,Genetics ,Biodefense ,Emerging Infectious Diseases ,Vaccine Related ,Prevention ,Pneumonia & Influenza ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Inflammatory and immune system ,Adult ,Autoimmune Diseases ,Communicable Diseases ,Dendritic Cells ,Escherichia coli ,Female ,Gene-Environment Interaction ,Genetic Loci ,Genome-Wide Association Study ,HEK293 Cells ,Host-Pathogen Interactions ,Humans ,Influenza A virus ,Interferon Regulatory Factor-7 ,Interferon-beta ,Lipopolysaccharides ,Male ,Middle Aged ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,STAT Transcription Factors ,Transcriptome ,Young Adult ,General Science & Technology - Abstract
Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and computational approaches were applied to determine the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells. We identified 121 common genetic variants associated in cis with variation in expression responses to Escherichia coli lipopolysaccharide, influenza, or interferon-β (IFN-β). We localized and validated causal variants to binding sites of pathogen-activated STAT (signal transducer and activator of transcription) and IRF (IFN-regulatory factor) transcription factors. We also identified a common variant in IRF7 that is associated in trans with type I IFN induction in response to influenza infection. Our results reveal common alleles that explain interindividual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases.
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- 2014
14. Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer’s human brains
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Klein, Hans-Ulrich, McCabe, Cristin, Gjoneska, Elizabeta, Sullivan, Sarah E., Kaskow, Belinda J., Tang, Anna, Smith, Robert V., Xu, Jishu, Pfenning, Andreas R., Bernstein, Bradley E., Meissner, Alexander, Schneider, Julie A., Mostafavi, Sara, Tsai, Li-Huei, Young-Pearse, Tracy L., Bennett, David A., and De Jager, Philip L.
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- 2019
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15. Author Correction: Nuclei multiplexing with barcoded antibodies for single-nucleus genomics
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Gaublomme, Jellert T., Li, Bo, McCabe, Cristin, Knecht, Abigail, Yang, Yiming, Drokhlyansky, Eugene, Van Wittenberghe, Nicholas, Waldman, Julia, Dionne, Danielle, Nguyen, Lan, De Jager, Philip L., Yeung, Bertrand, Zhao, Xinfang, Habib, Naomi, Rozenblatt-Rosen, Orit, and Regev, Aviv
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- 2020
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16. A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease
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Mostafavi, Sara, Gaiteri, Chris, Sullivan, Sarah E., White, Charles C., Tasaki, Shinya, Xu, Jishu, Taga, Mariko, Klein, Hans-Ulrich, Patrick, Ellis, Komashko, Vitalina, McCabe, Cristin, Smith, Robert, Bradshaw, Elizabeth M., Root, David E., Regev, Aviv, Yu, Lei, Chibnik, Lori B., Schneider, Julie A., Young-Pearse, Tracy L., Bennett, David A., and De Jager, Philip L.
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- 2018
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17. An xQTL map integrates the genetic architecture of the human brain's transcriptome and epigenome
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Ng, Bernard, White, Charles C, Klein, Hans-Ulrich, Sieberts, Solveig K, McCabe, Cristin, Patrick, Ellis, Xu, Jishu, Yu, Lei, Gaiteri, Chris, Bennett, David A, Mostafavi, Sara, and De Jager, Philip L
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- 2017
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18. Nuclei multiplexing with barcoded antibodies for single-nucleus genomics
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Gaublomme, Jellert T., Li, Bo, McCabe, Cristin, Knecht, Abigail, Yang, Yiming, Drokhlyansky, Eugene, Van Wittenberghe, Nicholas, Waldman, Julia, Dionne, Danielle, Nguyen, Lan, De Jager, Philip L., Yeung, Bertrand, Zhao, Xinfang, Habib, Naomi, Rozenblatt-Rosen, Orit, and Regev, Aviv
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- 2019
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19. Genetic architecture of age-related cognitive decline in African Americans
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Raj, Towfique, Chibnik, Lori B., McCabe, Cristin, Wong, Andus, Replogle, Joseph M., Yu, Lei, Gao, Sujuan, Unverzagt, Frederick W., Stranger, Barbara, Murrell, Jill, Barnes, Lisa, Hendrie, Hugh C., Foroud, Tatiana, Krichevsky, Anna, Bennett, David A., Hall, Kathleen S., Evans, Denis A., and De Jager, Philip L.
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- 2017
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20. Genes and Environment in Multiple Sclerosis Project: A Platform to Investigate Multiple Sclerosis Risk
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Xia, Zongqi, White, Charles C., Owen, Emily K., Von Korff, Alina, Clarkson, Sarah R., McCabe, Cristin A., Cimpean, Maria, Winn, Phoebe A., Hoesing, Ashley, Steele, Sonya U., Cortese, Irene C. M., Chitnis, Tanuja, Weiner, Howard L., Reich, Daniel S., Chibnik, Lori B., and De Jager, Philip L.
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- 2016
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21. IMMUNOGENETICS: Intersection of population variation and autoimmunity genetics in human T cell activation
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Ye, Chun Jimmie, Feng, Ting, Kwon, Ho-Keun, Raj, Towfique, Wilson, Michael, Asinovski, Natasha, McCabe, Cristin, Lee, Michelle H., Frohlich, Irene, Paik, Hyun-il, Zaitlen, Noah, Hacohen, Nir, Stranger, Barbara, Jager, Philip De, Mathis, Diane, Regev, Aviv, and Benoist, Christophe
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- 2014
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22. Genetic Susceptibility for Alzheimer Disease Neuritic Plaque Pathology
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Shulman, Joshua M., Chen, Kewei, Keenan, Brendan T., Chibnik, Lori B., Fleisher, Adam, Thiyyagura, Pradeep, Roontiva, Auttawut, McCabe, Cristin, Patsopoulos, Nikolaos A., Corneveaux, Jason J., Yu, Lei, Huentelman, Matthew J., Evans, Denis A., Schneider, Julie A., Reiman, Eric M., De Jager, Philip L., and Bennett, David A.
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- 2013
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23. Cellular network perturbations point to a new microglia‐astrocyte community accelerating Alzheimer's disease progression.
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Green, Gilad Sahar, Fujita, Masashi, Yang, Hyun‐Sik, McCabe, Cristin, Taga, Mariko, Cain, Anael, Zeng, Lu, Regev, Aviv, Bennett, David A, Menon, Vilas, Habib, Naomi, and De Jager, Philip L
- Abstract
Background: Alzheimer's Disease (AD) is a fatal neurodegenerative disease where abnormal accumulation of amyloid‐β and tau aggregates drive neurodegeneration and leads to cognitive impairment, dementia and eventually death. Combining results from recent studies, each finding a novel AD‐associated cell state of different non‐neuronal cell types, suggests a system level change of the cellular environment of the AD brain and its potential role in disease outcome. Method: To better understand the dynamics of the cellular environment in aging human brains and AD, we applied single‐nucleus RNA‐sequencing to profile 424 aging brains of individuals across different clinicopathological characteristics. We characterized the cellular diversity within the aging human prefrontal cortex, resulting in a detailed atlas of ∼1.7 million cells classified into 95 cellular subsets of different cell types, including rare populations of microglia and astrocytes. Results: Quantifying variations across individuals, we uncovered multiple cell subsets associated with disease pathologies and cognitive impairment. Of these, we prioritize an uncommon Microglial subset 13 (Mic.13, average 3.2% of microglia) and Astrocyte subset 10 (Ast.10, average 3.8% of astrocytes). Mic.13 expresses AD risk gene TREM2 and microglial markers linked to AD (e.g. APOE, SPP1), and its proportion is strongly associated with AD pathologies, amyloid‐β plaques and neurofibrillary tangles, and cognitive decline. Applying a mediation model, we showed that Mic.13 partially mediates the effect of amyloid‐β on tau (proportion mediated [p.m.] = 18%). While the impact of Mic.13 on cognitive decline is largely mediated by tau (p.m. = 43%), an additional subset highlighted by our analysis Ast.10, associated with both tau and cognitive decline, partially mediates the impact of tau and Mic.13 on cognitive decline (p.m. = 7.2% and p.m. = 12% respectively). Integration of all cellular states revealed an intricate network of multi‐cellular communities, each composed of multiple states of different cell types. Investigating the dynamics of the cellular communities in the aging brain and along disease progression, uncovered unique trajectories spanning from a healthy to diseased brains. Conclusion: Our charted atlas of the cellular environment and modelling of the cellular dynamics supports a system level change underlying AD, with an active role for multiple cell types in disease progression, and highlights novel research directions and potential therapeutic targets. [ABSTRACT FROM AUTHOR]
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- 2022
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24. Dissecting the role of non-coding RNAs in the accumulation of amyloid and tau neuropathologies in Alzheimer's disease.
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Patrick, Ellis, Rajagopal, Sathyapriya, Hon-Kit Andus Wong, McCabe, Cristin, Jishu Xu, Tang, Anna, Imboywa, Selina H., Schneider, Julie A., Pochet, Nathalie, Krichevsky, Anna M., Chibnik, Lori B., Bennett, David A., and De Jager, Philip L.
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NON-coding RNA ,ALZHEIMER'S disease ,AMYLOID ,MICRORNA ,LINCRNA ,NEUROFIBRILLARY tangles - Abstract
Background: Given multiple studies of brain microRNA (miRNA) in relation to Alzheimer's disease (AD) with few consistent results and the heterogeneity of this disease, the objective of this study was to explore their mechanism by evaluating their relation to different elements of Alzheimer's disease pathology, confounding factors and mRNA expression data from the same subjects in the same brain region. Methods: We report analyses of expression profiling of miRNA (n = 700 subjects) and lincRNA (n = 540 subjects) from the dorsolateral prefrontal cortex of individuals participating in two longitudinal cohort studies of aging. Results: We confirm the association of two well-established miRNA (miR-132, miR-129) with pathologic AD in our dataset and then further characterize this association in terms of its component neuritic β-amyloid plaques and neurofibrillary tangle pathologies. Additionally, we identify one new miRNA (miR-99) and four lincRNA that are associated with these traits. Many other previously reported associations of microRNA with AD are associated with the confounders quantified in our longitudinal cohort. Finally, by performing analyses integrating both miRNA and RNA sequence data from the same individuals (525 samples), we characterize the impact of AD associated miRNA on human brain expression: we show that the effects of miR-132 and miR-129-5b converge on certain genes such as EP300 and find a role for miR200 and its target genes in AD using an integrated miRNA/mRNA analysis. Conclusions: Overall, miRNAs play a modest role in human AD, but we observe robust evidence that a small number of miRNAs are responsible for specific alterations in the cortical transcriptome that are associated with AD. [ABSTRACT FROM AUTHOR]
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- 2017
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25. Methylation profiles in peripheral blood CD4+ lymphocytes versus brain: The relation to Alzheimer's disease pathology.
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Yu, Lei, Chibnik, Lori B., Yang, Jingyun, McCabe, Cristin, Xu, Jishu, Schneider, Julie A., De Jager, Philip L., and Bennett, David A.
- Abstract
Introduction We investigated the change in DNA methylation in peripheral blood CD4+ lymphocytes over time, examined the relation between CD4+ lymphocytes and brain methylation, and compared their associations with AD pathology. Methods Genome-wide methylation was measured three times in 41 older persons using Illumina Infinium HumanMethylation450 array. The two CD4+ lymphocytes measures were at study baseline and proximate to death. Brain tissue came from frozen dorsolateral prefrontal cortex. Results Global methylation features were conserved across tissue. At individual CpG sites, methylation level was concordant between the two CD4+ lymphocytes but more diffuse between CD4+ lymphocytes and brain. Previous associations of brain methylation with neuritic plaques at target methylation sites were not replicated in CD4+ lymphocytes. Discussion There is no strong evidence of change in CD4+ lymphocytes methylation among older persons over an average of 7.5 years. Methylation associations with AD pathology found in neocortex are not directly reflected in CD4+ lymphocytes. [ABSTRACT FROM AUTHOR]
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- 2016
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- View/download PDF
26. NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies.
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Ali, Yousuf O., Allen, Hunter M., Yu, Lei, Li-Kroeger, David, Bakhshizadehmahmoudi, Dena, Hatcher, Asante, McCabe, Cristin, Xu, Jishu, Bjorklund, Nicole, Taglialatela, Giulio, Bennett, David A., De Jager, Philip L., Shulman, Joshua M., Bellen, Hugo J., and Lu, Hui-Chen
- Subjects
NICOTINAMIDE ,MONONUCLEOSIS ,NEURODEGENERATION ,DEGENERATION (Pathology) ,MESSENGER RNA - Abstract
Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is neuroprotective in numerous preclinical models of neurodegeneration. Here, we show that brain nmnat2 mRNA levels correlate positively with global cognitive function and negatively with AD pathology. In AD brains, NMNAT2 mRNA and protein levels are reduced. NMNAT2 shifts its solubility and colocalizes with aggregated Tau in AD brains, similar to chaperones, which aid in the clearance or refolding of misfolded proteins. Investigating the mechanism of this observation, we discover a novel chaperone function of NMNAT2, independent from its enzymatic activity. NMNAT2 complexes with heat shock protein 90 (HSP90) to refold aggregated protein substrates. NMNAT2’s refoldase activity requires a unique C-terminal ATP site, activated in the presence of HSP90. Furthermore, deleting NMNAT2 function increases the vulnerability of cortical neurons to proteotoxic stress and excitotoxicity. Interestingly, NMNAT2 acts as a chaperone to reduce proteotoxic stress, while its enzymatic activity protects neurons from excitotoxicity. Taken together, our data indicate that NMNAT2 exerts its chaperone or enzymatic function in a context-dependent manner to maintain neuronal health. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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27. EXPRESSION QTL ANALYSIS FROM PRIMARY IMMUNE CELLS IDENTIFIES NOVEL REGULATORY EFFECTS UNDERLYING ALZHEIMER'S DISEASE SUSCEPTIBILITY
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Raj, Towfique, Replogle, Joseph M., Ryan, Katie, Chibnik, Lori, Ye, Jimmie, Mostafavi, Sara, Lee, Mark, Rothamel, Katie, McCabe, Cristin, Von Korff, Alina, Bradshaw, Elizabeth M., Evans, Denis, Bennett, David, Benoist, Christophe, Stranger, Barbara, and De Jager, Philip
- Published
- 2014
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28. Correlation between CpG DNA methylation levels in peripheral CD4+ T cells and dorsal lateral prefrontal cortex tissue
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Rosenkrantz, Laura, Srivastava, Gyan, Kaliszewska, Anna, Imboywa, Selina, McCabe, Cristin, Schneider, Julie, Bennett, David, and De Jager, Philip
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- 2013
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29. Characterizing the role of MICRO-RNA expression in the aging human brain transcriptome
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Rajagopal, Sathyapriya, Pochet, Nathalie, Srivastava, Gyan, Rosenkratz, Laura, McCabe, Cristin, Bennett, David, and De Jager, Philip
- Published
- 2013
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30. Genome-wide association study and admixture mapping of age-related cognitive decline in African-Americans
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Raj, Towfique, Chibnik, Lori, McCabe, Cristin, Stranger, Barbara, Barnes, Lisa L., Weir, David, Mayeux, Richard, Foroud, Tatiana, Bennett, David, Hall, Kathleen Steele, Murrell, Jill, Evans, Denis, and De Jager, Philip
- Published
- 2013
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31. Genetic architecture of age-related cognitive decline in African Americans
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Raj, Towfique, Chibnik, Lori B., McCabe, Cristin, Wong, Andus, Replogle, Joseph M., Yu, Lei, Gao, Sujuan, Unverzagt, Frederick W., Stranger, Barbara, Murrell, Jill, Barnes, Lisa, Hendrie, Hugh C., Foroud, Tatiana, Krichevsky, Anna, Bennett, David A., Hall, Kathleen S., Evans, Denis A., and De Jager, Philip L.
- Abstract
Objective: To identify genetic risk factors associated with susceptibility to age-related cognitive decline in African Americans (AAs). Methods: We performed a genome-wide association study (GWAS) and an admixture-mapping scan in 3,964 older AAs from 5 longitudinal cohorts; for each participant, we calculated a slope of an individual's global cognitive change from neuropsychological evaluations. We also performed a pathway-based analysis of the age-related cognitive decline GWAS. Results: We found no evidence to support the existence of a genomic region which has a strongly different contribution to age-related cognitive decline in African and European genomes. Known Alzheimer disease (AD) susceptibility variants in the ABCA7 and MS4A loci do influence this trait in AAs. Of interest, our pathway-based analyses returned statistically significant results highlighting a shared risk from lipid/metabolism and protein tyrosine signaling pathways between cognitive decline and AD, but the role of inflammatory pathways is polarized, being limited to AD susceptibility. Conclusions: The genetic architecture of aging-related cognitive in AA individuals is largely similar to that of individuals of European descent. In both populations, we note a surprising lack of enrichment for immune pathways in the genetic risk for cognitive decline, despite strong enrichment of these pathways among genetic risk factors for AD.
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- 2016
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32. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci
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De Jager, Philip Lawrence, Srivastava, Gyan, Lunnon, Katie, Burgess, Jeremy, Schalkwyk, Leonard C, Yu, Lei, Eaton, Matthew L, Keenan, Brendan T, Ernst, Jason, McCabe, Cristin, Tang, Anna, Raj, Towfique, Replogle, Joseph, Brodeur, Wendy, Gabriel, Stacey, Chai, High S, Younkin, Curtis, Younkin, Steven G, Zou, Fanggeng, Szyf, Moshe, Epstein, Charles B, Schneider, Julie A, Bernstein, Bradley E., Meissner, Alexander, Ertekin-Taner, Nilufer, Chibnik, Lori, Kellis, Manolis, Mill, Jonathan, and Bennett, David A
- Abstract
We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network., Stem Cell and Regenerative Biology
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- 2014
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33. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
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Beecham, Ashley H, Patsopoulos, Nikolaos A, Xifara, Dionysia K, Davis, Mary F, Kemppinen, Anu, Cotsapas, Chris, Shahi, Tejas S, Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, D’alfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F, Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R, Hintzen, Rogier, Barcellos, Lisa F, Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Søndergaard, Helle Bach, Baker, Amie, Band, Gavin, Baranzini, Sergio E, Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Céline, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas M C, Blackburn, Hannah, Bomfim, Izaura L, Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J, Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G, Coman, Irène, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce A C, Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R, Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T, Donnelly, Peter, Dubois, Bénédicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y, Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah E, Jagodic, Maja, Jelčić, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, Langford, Cordelia, Larsson, Malin, Lathrop, Mark, Lebrun-Frenay, Christine, Lechner-Scott, Jeannette, Lee, Michelle H, Leone, Maurizio A, Leppä, Virpi, Liberatore, Giuseppe, Lie, Benedicte A, Lill, Christina M, Lindén, Magdalena, Link, Jenny, Luessi, Felix, Lycke, Jan, Macciardi, Fabio, Männistö, Satu, Manrique, Clara P, Martin, Roland, Martinelli, Vittorio, Mason, Deborah, Mazibrada, Gordon, McCabe, Cristin, Mero, Inger-Lise, Mescheriakova, Julia, Moutsianas, Loukas, Myhr, Kjell-Morten, Nagels, Guy, Nicholas, Richard, Nilsson, Petra, Piehl, Fredrik, Pirinen, Matti, Price, Siân E, Quach, Hong, Reunanen, Mauri, Robberecht, Wim, Robertson, Neil P, Rodegher, Mariaemma, Rog, David, Salvetti, Marco, Schnetz-Boutaud, Nathalie C, Sellebjerg, Finn, Selter, Rebecca C, Schaefer, Catherine, Shaunak, Sandip, Shen, Ling, Shields, Simon, Siffrin, Volker, Slee, Mark, Sorensen, Per Soelberg, Sorosina, Melissa, Sospedra, Mireia, Spurkland, Anne, Strange, Amy, Sundqvist, Emilie, Thijs, Vincent, Thorpe, John, Ticca, Anna, Tienari, Pentti, van Duijn, Cornelia, Visser, Elizabeth M, Vucic, Steve, Westerlind, Helga, Wiley, James S, Wilkins, Alastair, Wilson, James F, Winkelmann, Juliane, Zajicek, John, Zindler, Eva, Haines, Jonathan L, Pericak-Vance, Margaret A, Ivinson, Adrian J, Stewart, Graeme, Hafler, David, Hauser, Stephen L, Compston, Alastair, McVean, Gil, De Jager, Philip, Sawcer, Stephen, and McCauley, Jacob L
- Abstract
Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 1.0 × 10-4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 multiple sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex. With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals.
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- 2013
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34. A cellular and spatial map of the choroid plexus across brain ventricles and ages.
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Dani, Neil, Herbst, Rebecca H., McCabe, Cristin, Green, Gilad S., Kaiser, Karol, Head, Joshua P., Cui, Jin, Shipley, Frederick B., Jang, Ahram, Dionne, Danielle, Nguyen, Lan, Rodman, Christopher, Riesenfeld, Samantha J., Prochazka, Jan, Prochazkova, Michaela, Sedlacek, Radislav, Zhang, Feng, Bryja, Vitezslav, Rozenblatt-Rosen, Orit, and Habib, Naomi
- Subjects
- *
CEREBRAL ventricles , *CHOROID plexus , *AGING , *CELL communication , *CEREBROSPINAL fluid , *EPITHELIAL cells - Abstract
The choroid plexus (ChP) in each brain ventricle produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. Here, we construct a single-cell and spatial atlas of each ChP in the developing, adult, and aged mouse brain. We delineate diverse cell types, subtypes, cell states, and expression programs in epithelial and mesenchymal cells across ages and ventricles. In the developing ChP, we predict a common progenitor pool for epithelial and neuronal cells, validated by lineage tracing. Epithelial and fibroblast cells show regionalized expression by ventricle, starting at embryonic stages and persisting with age, with a dramatic transcriptional shift with maturation, and a smaller shift in each aged cell type. With aging, epithelial cells upregulate host-defense programs, and resident macrophages upregulate interleukin-1β (IL-1β) signaling genes. Our atlas reveals cellular diversity, architecture and signaling across ventricles during development, maturation, and aging of the ChP-brain barrier. [Display omitted] • A detailed map of mouse choroid plexus (ChP) cells across ventricles and ages • Ventricle- and age-dependent expression programs in epithelial and fibroblast cells • A common progenitor pool for embryonic epithelial and neuronal cells uncovered • Cell-cell interaction networks found cell-type-specific IL-1β signaling in aged ChP Single-cell and spatial atlas of the developing, adult, and aged mouse brain choroid plexus uncovers its cellular diversity, organization, and signaling to provide insights into the development and function of this essential brain barrier. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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35. Intersection of population variation and autoimmunity genetics in human T cell activation.
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Chun Jimmie Ye, Ting Feng, Ho-Keun Kwon, Raj, Towfique, Wilson, Michael, Asmovski, Natasha, McCabe, Cristin, Lee, Michelle H., Fröhlich, Irene, Hyun-il Paik, Zaitlen, Noah, Hacohen, Nir, Stranger, Barbara, De Jager, Philip, Mathis, Diane, Regev, Aviv, and Benoist, Christophe
- Subjects
- *
IMMUNOGENETICS , *AUTOIMMUNITY , *T cells - Abstract
An abstract of the article “Intersection of Population Variation and Autoimmunity Genetics in Human T Cell Activation" by Chun Jimmie Ye, Ting Feng, and Ho-Keun Kwon et al. is presented.
- Published
- 2014
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36. Cellular communities reveal trajectories of brain ageing and Alzheimer's disease.
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Green GS, Fujita M, Yang HS, Taga M, Cain A, McCabe C, Comandante-Lou N, White CC, Schmidtner AK, Zeng L, Sigalov A, Wang Y, Regev A, Klein HU, Menon V, Bennett DA, Habib N, and De Jager PL
- Abstract
Alzheimer's disease (AD) has recently been associated with diverse cell states
1-11 , yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-β proteinopathy while the other mediates the effect of amyloid-β on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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37. Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease.
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Green GS, Fujita M, Yang HS, Taga M, McCabe C, Cain A, White CC, Schmidtner AK, Zeng L, Wang Y, Regev A, Menon V, Bennett DA, Habib N, and De Jager PL
- Abstract
Alzheimer's Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brain's cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We identified two distinct lipid-associated microglial subpopulations, one contributed to amyloid-β proteinopathy while the other mediated the effect of amyloid-β in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities. Older individuals are engaged in one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging. Thus, we provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.
- Published
- 2023
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38. Multi-region brain transcriptomes uncover two subtypes of aging individuals with differences in Alzheimer risk and the impact of APOEε4 .
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Lee AJ, Ma Y, Yu L, Dawe RJ, McCabe C, Arfanakis K, Mayeux R, Bennett DA, Klein HU, and De Jager PL
- Abstract
The heterogeneity of the older population suggests the existence of subsets of individuals which share certain brain molecular features and respond differently to risk factors for Alzheimer's disease, but this population structure remains poorly defined. Here, we performed an unsupervised clustering of individuals with multi-region brain transcriptomes to assess whether a broader approach, simultaneously considering data from multiple regions involved in cognition would uncover such subsets. We implemented a canonical correlation-based analysis in a Discovery cohort of 459 participants from two longitudinal studies of cognitive aging that have RNA sequence profiles in three brain regions. 690 additional participants that have data in only one or two of these regions were used in the Replication effort. These clustering analyses identified two meta-clusters, MC-1 and MC-2. The two sets of participants differ primarily in their trajectories of cognitive decline, with MC-2 having a delay of 3 years to the median age of incident dementia. This is due, in part, to a greater impact of tau pathology on neuronal chromatin architecture and to broader brain changes including greater loss of white matter integrity in MC-1. Further evidence of biological differences includes a significantly larger impact of APOEε4 risk on cognitive decline in MC-1. These findings suggest that our proposed population structure captures an aspect of the more distributed molecular state of the aging brain that either enhances the effect of risk factors in MC-1 or of protective effects in MC-2. These observations may inform the design of therapeutic development efforts and of trials as both become increasingly more targeted molecularly. One Sentence Summary: There are two types of aging brains, with one being more vulnerable to APOEε4 and subsequent neuronal dysfunction and cognitive loss.
- Published
- 2023
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39. A single-cell and spatial atlas of autopsy tissues reveals pathology and cellular targets of SARS-CoV-2.
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Delorey TM, Ziegler CGK, Heimberg G, Normand R, Yang Y, Segerstolpe A, Abbondanza D, Fleming SJ, Subramanian A, Montoro DT, Jagadeesh KA, Dey KK, Sen P, Slyper M, Pita-Juárez YH, Phillips D, Bloom-Ackerman Z, Barkas N, Ganna A, Gomez J, Normandin E, Naderi P, Popov YV, Raju SS, Niezen S, Tsai LT, Siddle KJ, Sud M, Tran VM, Vellarikkal SK, Amir-Zilberstein L, Atri DS, Beechem J, Brook OR, Chen J, Divakar P, Dorceus P, Engreitz JM, Essene A, Fitzgerald DM, Fropf R, Gazal S, Gould J, Grzyb J, Harvey T, Hecht J, Hether T, Jane-Valbuena J, Leney-Greene M, Ma H, McCabe C, McLoughlin DE, Miller EM, Muus C, Niemi M, Padera R, Pan L, Pant D, Pe'er C, Pfiffner-Borges J, Pinto CJ, Plaisted J, Reeves J, Ross M, Rudy M, Rueckert EH, Siciliano M, Sturm A, Todres E, Waghray A, Warren S, Zhang S, Zollinger DR, Cosimi L, Gupta RM, Hacohen N, Hide W, Price AL, Rajagopal J, Tata PR, Riedel S, Szabo G, Tickle TL, Hung D, Sabeti PC, Novak R, Rogers R, Ingber DE, Jiang ZG, Juric D, Babadi M, Farhi SL, Stone JR, Vlachos IS, Solomon IH, Ashenberg O, Porter CBM, Li B, Shalek AK, Villani AC, Rozenblatt-Rosen O, and Regev A
- Abstract
The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and cellular responses associated with COVID-19 infection, symptoms, and lethality. To address this, we collected tissues from 11 organs during the clinical autopsy of 17 individuals who succumbed to COVID-19, resulting in a tissue bank of approximately 420 specimens. We generated comprehensive cellular maps capturing COVID-19 biology related to patients' demise through single-cell and single-nucleus RNA-Seq of lung, kidney, liver and heart tissues, and further contextualized our findings through spatial RNA profiling of distinct lung regions. We developed a computational framework that incorporates removal of ambient RNA and automated cell type annotation to facilitate comparison with other healthy and diseased tissue atlases. In the lung, we uncovered significantly altered transcriptional programs within the epithelial, immune, and stromal compartments and cell intrinsic changes in multiple cell types relative to lung tissue from healthy controls. We observed evidence of: alveolar type 2 (AT2) differentiation replacing depleted alveolar type 1 (AT1) lung epithelial cells, as previously seen in fibrosis; a concomitant increase in myofibroblasts reflective of defective tissue repair; and, putative TP63
+ intrapulmonary basal-like progenitor (IPBLP) cells, similar to cells identified in H1N1 influenza, that may serve as an emergency cellular reserve for severely damaged alveoli. Together, these findings suggest the activation and failure of multiple avenues for regeneration of the epithelium in these terminal lungs. SARS-CoV-2 RNA reads were enriched in lung mononuclear phagocytic cells and endothelial cells, and these cells expressed distinct host response transcriptional programs. We corroborated the compositional and transcriptional changes in lung tissue through spatial analysis of RNA profiles in situ and distinguished unique tissue host responses between regions with and without viral RNA, and in COVID-19 donor tissues relative to healthy lung. Finally, we analyzed genetic regions implicated in COVID-19 GWAS with transcriptomic data to implicate specific cell types and genes associated with disease severity. Overall, our COVID-19 cell atlas is a foundational dataset to better understand the biological impact of SARS-CoV-2 infection across the human body and empowers the identification of new therapeutic interventions and prevention strategies., Competing Interests: Competing Interests P.D., R.F., E.M.M., M.R., E.H.R., L.P., T.He., J.R., J.B., and S.W. are employees and stockholders at Nanostring Technologies Inc. D.Z., is a former employee and stockholder at NanoString Technologies. N.H., holds equity in BioNTech and Related Sciences. T.H.is an employee and stockholder of Prime Medicine as of Oct. 13, 2020. G.H. is an employee of Genentech as of Nov 16, 2020. R.N. is a founder, shareholder, and member of the board at Rhinostics Inc. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov until July 31, 2020. From August 1, 2020, A.R. is an employee of Genentech. From October 19, 2020, O.R.-R is an employee of Genentech. P.C.S is a co-founder and shareholder of Sherlock Biosciences, and a Board member and shareholder of Danaher Corporation. A.K.S. reports compensation for consulting and/or SAB membership from Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Ochre Bio, and Dahlia Biosciences. Z.G.J. reports grant support from Gilead Science, Pfizer, compensation for consulting from Olix Pharmaceuticals. Y.V.P. reports grant support from Enanta Pharmaceuticals, CymaBay Therapeutics, Morphic Therapeutic; consulting and/or SAB in Ambys Medicines, Morphic Therapeutics, Enveda Therapeutics, BridgeBio Pharma, as well as being an Editor – American Journal of Physiology-Gastrointestinal and Liver Physiology. GS reports consultant service in Alnylam Pharmaceuticals, Merck, Generon, Glympse Bio, Inc., Mayday Foundation, Novartis Pharmaceuticals, Quest Diagnostics, Surrozen, Terra Firma, Zomagen Bioscience, Pandion Therapeutics, Inc. Durect Corporation; royalty from UpToDate Inc., and Editor service in Hepatology Communications. P.R.T. receives consulting fees from Cellarity Inc., and Surrozen Inc., for work not related to this manuscript.- Published
- 2021
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40. A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research.
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De Jager PL, Ma Y, McCabe C, Xu J, Vardarajan BN, Felsky D, Klein HU, White CC, Peters MA, Lodgson B, Nejad P, Tang A, Mangravite LM, Yu L, Gaiteri C, Mostafavi S, Schneider JA, and Bennett DA
- Subjects
- Aged, Aged, 80 and over, Aging, Chromatin Immunoprecipitation, DNA Methylation, Female, Humans, Male, Metabolome, Metabolomics, Sequence Analysis, RNA, Alzheimer Disease genetics, Alzheimer Disease physiopathology, Frontal Lobe physiology, Genome, Human, Proteomics
- Abstract
We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a quantitative, structured neuropathologic examination after death. They include over 3,322 subjects. Here, we outline the first generation of data including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702). Generation of other omic data including ATACseq, proteomic and metabolomics profiles is ongoing. Thanks to its prospective design and recruitment of older, non-demented individuals, these data can be repurposed to investigate a large number of syndromic and quantitative neuroscience phenotypes. The many subjects that are cognitively non-impaired at death also offer insights into the biology of the human brain in older non-impaired individuals.
- Published
- 2018
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41. Methylation profiles in peripheral blood CD4+ lymphocytes versus brain: The relation to Alzheimer's disease pathology.
- Author
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Yu L, Chibnik LB, Yang J, McCabe C, Xu J, Schneider JA, De Jager PL, and Bennett DA
- Subjects
- Aged, Alzheimer Disease genetics, Biomarkers blood, Chromatin metabolism, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Mental Status and Dementia Tests, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, White People, Alzheimer Disease blood, Alzheimer Disease pathology, CD4-Positive T-Lymphocytes metabolism, DNA Methylation, Prefrontal Cortex metabolism, Prefrontal Cortex pathology
- Abstract
Introduction: We investigated the change in DNA methylation in peripheral blood CD4+ lymphocytes over time, examined the relation between CD4+ lymphocytes and brain methylation, and compared their associations with AD pathology., Methods: Genome-wide methylation was measured three times in 41 older persons using Illumina Infinium HumanMethylation450 array. The two CD4+ lymphocytes measures were at study baseline and proximate to death. Brain tissue came from frozen dorsolateral prefrontal cortex., Results: Global methylation features were conserved across tissue. At individual CpG sites, methylation level was concordant between the two CD4+ lymphocytes but more diffuse between CD4+ lymphocytes and brain. Previous associations of brain methylation with neuritic plaques at target methylation sites were not replicated in CD4+ lymphocytes., Discussion: There is no strong evidence of change in CD4+ lymphocytes methylation among older persons over an average of 7.5 years. Methylation associations with AD pathology found in neocortex are not directly reflected in CD4+ lymphocytes., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
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