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2. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Author

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

Subjects
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.

Published
2019

3. Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection

Author

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

Subjects
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.

Published
2018

4. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets

Author

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

Published
2021
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5. Atlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue

Author

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.

Published
2021
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6. Intersection of population variation and autoimmunity genetics in human T cell activation

Author

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

Subjects
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.

Published
2014

7. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci

Author

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

Subjects
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.

Published
2014

8. Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes

Author

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

Subjects
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.

Published
2014

9. Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells

Author

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

Subjects
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.

Published
2014

13. Abstract SY12-04: Multicellular spatial community featuring a novel neuronal-like malignant phenotype is enriched in pancreatic cancer after neoadjuvant chemotherapy and radiotherapy

Author

Hwang, William L., primary, Jagadeesh, Karthik A., additional, Guo, Jimmy A., additional, Hoffman, Hannah I., additional, Shiau, Carina, additional, Su, Jennifer, additional, Yadollahpour, Payman, additional, Reeves, Jason W., additional, Kim, Youngmi, additional, Kim, Sean, additional, Gregory, Mark, additional, Divakar, Prajan, additional, Miller, Eric, additional, Rhodes, Michael, additional, Warren, Sarah, additional, Rueckert, Erroll, additional, Fuhrman, Kit, additional, Zollinger, Daniel R., additional, Fropf, Robin, additional, Beechem, Joseph M., additional, Mehta, Arnav, additional, Delorey, Toni, additional, McCabe, Cristin, additional, Barth, Jaimie L., additional, Zelga, Piotr, additional, Ferrone, Cristina R., additional, Qadan, Motaz, additional, Lillemoe, Keith D., additional, Jain, Rakesh K., additional, Wo, Jennifer Y., additional, Hong, Theodore S., additional, Xavier, Ramnik, additional, Rozenblatt-Rosen, Orit, additional, Aguirre, Andrew J., additional, Castillo, Carlos Fernandez-Del, additional, Liss, Andrew S., additional, Mino-Kenudson, Mari, additional, Ting, David T., additional, Jacks, Tyler, additional, and Regev, Aviv, additional

Published
2022
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14. A cellular and spatial map of the choroid plexus across brain ventricles and ages

Author

Dani, Neil, primary, Herbst, Rebecca H., additional, McCabe, Cristin, additional, Green, Gilad S., additional, Kaiser, Karol, additional, Head, Joshua P., additional, Cui, Jin, additional, Shipley, Frederick B., additional, Jang, Ahram, additional, Dionne, Danielle, additional, Nguyen, Lan, additional, Rodman, Christopher, additional, Riesenfeld, Samantha J., additional, Prochazka, Jan, additional, Prochazkova, Michaela, additional, Sedlacek, Radislav, additional, Zhang, Feng, additional, Bryja, Vitezslav, additional, Rozenblatt-Rosen, Orit, additional, Habib, Naomi, additional, Regev, Aviv, additional, and Lehtinen, Maria K., additional

Published
2021
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15. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Author

Mitrovič, Mitja, primary, Patsopoulos, Nikolaos A., additional, Beecham, Ashley H., additional, Dankowski, Theresa, additional, Goris, An, additional, Dubois, Bénédicte, additional, D’hooghe, Marie B., additional, Lemmens, Robin, additional, Van Damme, Philip, additional, Søndergaard, Helle Bach, additional, Sellebjerg, Finn, additional, Sorensen, Per Soelberg, additional, Ullum, Henrik, additional, Thørner, Lise W., additional, Werge, Thomas, additional, Saarela, Janna, additional, Cournu-Rebeix, Isabelle, additional, Damotte, Vincent, additional, Fontaine, Bertrand, additional, Guillot-Noel, Lena, additional, Lathrop, Mark, additional, Vukusik, Sandra, additional, Gourraud, Pierre-Antoine, additional, Andlauer, Till F.M., additional, Pongratz, Viola, additional, Buck, Dorothea, additional, Gasperi, Christiane, additional, Bayas, Antonios, additional, Heesen, Christoph, additional, Kümpfel, Tania, additional, Linker, Ralf, additional, Paul, Friedemann, additional, Stangel, Martin, additional, Tackenberg, Björn, additional, Bergh, Florian Then, additional, Warnke, Clemens, additional, Wiendl, Heinz, additional, Wildemann, Brigitte, additional, Zettl, Uwe, additional, Ziemann, Ulf, additional, Tumani, Hayrettin, additional, Gold, Ralf, additional, Grummel, Verena, additional, Hemmer, Bernhard, additional, Knier, Benjamin, additional, Lill, Christina M., additional, Luessi, Felix, additional, Dardiotis, Efthimios, additional, Agliardi, Cristina, additional, Barizzone, Nadia, additional, Mascia, Elisabetta, additional, Bernardinelli, Luisa, additional, Comi, Giancarlo, additional, Cusi, Daniele, additional, Esposito, Federica, additional, Ferrè, Laura, additional, Comi, Cristoforo, additional, Galimberti, Daniela, additional, Leone, Maurizio A., additional, Sorosina, Melissa, additional, Mescheriakova, Julia, additional, Hintzen, Rogier, additional, van Duijn, Cornelia, additional, Teunissen, Charlotte E., additional, Bos, Steffan D., additional, Myhr, Kjell-Morten, additional, Celius, Elisabeth G., additional, Lie, Benedicte A., additional, Spurkland, Anne, additional, Comabella, Manuel, additional, Montalban, Xavier, additional, Alfredsson, Lars, additional, Stridh, Pernilla, additional, Hillert, Jan, additional, Jagodic, Maja, additional, Piehl, Fredrik, additional, Jelčić, Ilijas, additional, Martin, Roland, additional, Sospedra, Mireia, additional, Ban, Maria, additional, Hawkins, Clive, additional, Hysi, Pirro, additional, Kalra, Seema, additional, Karpe, Fredrik, additional, Khadake, Jyoti, additional, Lachance, Genevieve, additional, Neville, Matthew, additional, Santaniello, Adam, additional, Caillier, Stacy J., additional, Calabresi, Peter A., additional, Cree, Bruce A.C., additional, Cross, Anne, additional, Davis, Mary F., additional, Haines, Jonathan L., additional, de Bakker, Paul I.W., additional, Delgado, Silvia, additional, Dembele, Marieme, additional, Edwards, Keith, additional, Fitzgerald, Kathryn C., additional, Hakonarson, Hakon, additional, Konidari, Ioanna, additional, Lathi, Ellen, additional, Manrique, Clara P., additional, Pericak-Vance, Margaret A., additional, Piccio, Laura, additional, Schaefer, Cathy, additional, McCabe, Cristin, additional, Weiner, Howard, additional, Goldstein, Jacqueline, additional, Olsson, Tomas, additional, Hadjigeorgiou, Georgios, additional, Taylor, Bruce, additional, Tajouri, Lotti, additional, Charlesworth, Jac, additional, Booth, David R., additional, Harbo, Hanne F., additional, Ivinson, Adrian J., additional, Hauser, Stephen L., additional, Compston, Alastair, additional, Stewart, Graeme, additional, Zipp, Frauke, additional, Barcellos, Lisa F., additional, Baranzini, Sergio E., additional, Martinelli-Boneschi, Filippo, additional, D’Alfonso, Sandra, additional, Ziegler, Andreas, additional, Oturai, Annette, additional, McCauley, Jacob L., additional, Sawcer, Stephen J., additional, Oksenberg, Jorge R., additional, De Jager, Philip L., additional, Kockum, Ingrid, additional, Hafler, David A., additional, and Cotsapas, Chris, additional

Published
2020
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16. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Author

Int Multiple Sclerosis Genetics, Mitrovic, Mitja, Patsopoulos, Nikoloas, Beecham, Ashley, Dankowski, Theresa, Goris, An, Dubois, Bénédicte, D'hooghe, Marie B, Lemmens, Robin, Van Damme, Philip, Bach Sondergaard, Helle, Sellebjerg, Finn, Soelberg Sorensen, Per, Ullum, Henrik, Thorner, Lise W, Werge, Thomas, Saarela, Janna, Cournu-Rebeix, Isabelle, Damotte, Vincent, Fontaine, Bertrand, Guillot-Noel, Lena, Lathrop, Mark, Vukusik, Sandra, Gourraud, Pierre-Antoine, Andlauer, Till FM, Pongratz, Viola, Buck, Dorothea, Gasperi, Christiane, Bayas, Antonios, Heesen, Christoph, Kümpfel, Tania, Linker, Ralf, Friedemann, Paul, Stangel, Martin, Tackenberg, Björn, Then Bergh, Florian, Warnke, Clemens, Wiendl, Heinz, Wildemann, Brigitte, Zettl, Uwe, Ziemann, Ulf, Tumani, Hayrettin, Gold, Ralf, Grummel, Verena, Hemmer, Bernhard, Knier, Benjamin, Lill, Christina, Luessi, Felix, Dardiotis, Efthimios, Agliardi, Cristina, Barizzone, Nadia, Mascia, Elisabetta, Bernardinelli, Luisa, Comi, Giancarlo, Cusi, Daniele, Esposito, Federica, Ferrè, Laura, Comi, Cristoforo, Galimberti, Daniela, Leone, Maurizio A, Sorosina, Melissa, Mescheriakova, Julia, Hintzen, Rogier, van Duijn, Cornelia, Theunissen, Charlotte E, Bos, Steffan D, Myhr, Kjell-Morten, Celius, Elisabeth G, Lie, Benedicte A, Spurkland, Anne, Comabella, Manuel, Montalban, Xavier, Alfredsson, Lars, Stridh, Pernilla, Hillert, Jan, Jagodic, Maja, Piehl, Fredrik, Jelcic, Ilijas, Martin, Roland, Sospedra, Mireia, Ban, Maria, Hawkins, Clive, Hysi, Pirro, Kalra, Seema, Karpe, Fredrik, Khadake, Jyoti, Lachance, Genevieve, Neville, Matthew, Santaniello, Adam, Caillier, Stacy J, Calavresi, Peter A, Cree, Bruce AC, Cross, Anne, Davis, Mary F, Haines, Jonathan L, de Bakker, Paul IW, Delgado, Silvia, Dembele, Marieme, Edwards, Keith, Fitzgerald, Kathryn C, Hakonarson, Hakon, Konidari, Ioanna, Lathi, Ellen, Manrique, Clara P, Pericak-Vance, Margaret A, Piccio, Laura, Schaefer, Cathy, McCabe, Cristin, Weiner, Howard, Goldstein, Jacqueline, Olsson, Tomas, Hadjigeorgiou, Georgios, Taylor, Bruce, Tajouri, Lotti, Charlesworth, Jac, Booth, David R, HArbo, Hanne F, Ivinson, Adrian J, Hauser, Stephen L, Compston, Alistair, Stewart, Graeme, Zipp, Frauke, Barcellos, Lisa F, Baranzini, Sergio E, Martinelli-Boneschi, Filippo, D'Alfonso, Sandra, Ziegler, Andreas, Oturai, Annette, McCauley, Jacob L, Sawcer, Stephen J, Oksenberg, Jorge R, De Jager, Philip L, Kockum, Ingrid, Hafler, David A, and Cotsapas, Chris

Subjects
Biochemistry & Molecular Biology, Science & Technology, REPLICATION, LINKAGE, Cell Biology, GENETIC RISK, GENOME-WIDE ASSOCIATION, VARIANTS, Life Sciences & Biomedicine, METAANALYSIS, POPULATION
Abstract

Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS. ispartof: CELL vol:175 issue:6 pages:1679-1695 ispartof: location:United States status: published

Published
2018

17. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Author

Mitrovič, Mitja, Patsopoulos, Nikolaos, Beecham, Ashley, Dankowski, Theresa, Goris, An, Dubois, Bénédicte, D’hooghe, Marie, Lemmens, Robin, Van Damme, Philip, Søndergaard, Helle Bach, Sellebjerg, Finn, Sorensen, Per Soelberg, Ullum, Henrik, Thørner, Lise, Werge, Thomas, Saarela, Janna, Cournu-Rebeix, Isabelle, Damotte, Vincent, Fontaine, Bertrand, Guillot-Noel, Lena, Lathrop, Mark, Vukusik, Sandra, Gourraud, Pierre-Antoine, Andlauer, Till F.M., Pongratz, Viola, Buck, Dorothea, Gasperi, Christiane, Bayas, Antonios, Heesen, Christoph, Kümpfel, Tania, Linker, Ralf, Paul, Friedemann, Stangel, Martin, Tackenberg, Björn, Bergh, Florian Then, Warnke, Clemens, Wiendl, Heinz, Wildemann, Brigitte, Zettl, Uwe, Ziemann, Ulf, Tumani, Hayrettin, Gold, Ralf, Grummel, Verena, Hemmer, Bernhard, Knier, Benjamin, Lill, Christina, Luessi, Felix, Dardiotis, Efthimios, Agliardi, Cristina, Barizzone, Nadia, Mascia, Elisabetta, Bernardinelli, Luisa, Comi, Giancarlo, Cusi, Daniele, Esposito, Federica, Ferrè, Laura, Comi, Cristoforo, Galimberti, Daniela, Leone, Maurizio, Sorosina, Melissa, Mescheriakova, Julia, Hintzen, Rogier, Van Duijn, Cornelia, Teunissen, Charlotte, Bos, Steffan, Myhr, Kjell-Morten, Celius, Elisabeth, Lie, Benedicte, Spurkland, Anne, Comabella, Manuel, Montalban, Xavier, Alfredsson, Lars, Stridh, Pernilla, Hillert, Jan, Jagodic, Maja, Piehl, Fredrik, Jelčić, Ilijas, Martin, Roland, Sospedra, Mireia, Ban, Maria, Hawkins, Clive, Hysi, Pirro, Kalra, Seema, Karpe, Fredrik, Khadake, Jyoti, Lachance, Genevieve, Neville, Matthew, Santaniello, Adam, Caillier, Stacy, Calabresi, Peter, Cree, Bruce A.C., Cross, Anne, Davis, Mary, Haines, Jonathan, de Bakker, Paul I.W., Delgado, Silvia, Dembele, Marieme, Edwards, Keith, Fitzgerald, Kathryn, Hakonarson, Hakon, Konidari, Ioanna, Lathi, Ellen, Manrique, Clara, Pericak-Vance, Margaret, Piccio, Laura, Schaefer, Cathy, McCabe, Cristin, Weiner, Howard, Goldstein, Jacqueline, Olsson, Tomas, Hadjigeorgiou, Georgios, Taylor, Bruce, Tajouri, Lotti, Charlesworth, Jac, Booth, David, Harbo, Hanne, Ivinson, Adrian, Hauser, Stephen, Compston, Alastair, Stewart, Graeme, Zipp, Frauke, Barcellos, Lisa, Baranzini, Sergio, Martinelli-Boneschi, Filippo, D’Alfonso, Sandra, Ziegler, Andreas, Oturai, Annette, McCauley, Jacob, Sawcer, Stephen, Oksenberg, Jorge, De Jager, Philip, Kockum, Ingrid, Hafler, David, Cotsapas, Chris, Søndergaard, Helle, Sorensen, Per, Andlauer, Till, Bergh, Florian, Cree, Bruce, De Bakker, Paul, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Centre de Recherche en Myologie

Subjects
[SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
Abstract

International audience; Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.

Published
2018

18. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Author

Mitrovič, Mitja, primary, Patsopoulos, Nikolaos A., additional, Beecham, Ashley H., additional, Dankowski, Theresa, additional, Goris, An, additional, Dubois, Bénédicte, additional, D’hooghe, Marie B., additional, Lemmens, Robin, additional, Van Damme, Philip, additional, Søndergaard, Helle Bach, additional, Sellebjerg, Finn, additional, Sorensen, Per Soelberg, additional, Ullum, Henrik, additional, Thørner, Lise W., additional, Werge, Thomas, additional, Saarela, Janna, additional, Cournu-Rebeix, Isabelle, additional, Damotte, Vincent, additional, Fontaine, Bertrand, additional, Guillot-Noel, Lena, additional, Lathrop, Mark, additional, Vukusik, Sandra, additional, Gourraud, Pierre-Antoine, additional, Andlauer, Till F.M., additional, Pongratz, Viola, additional, Buck, Dorothea, additional, Gasperi, Christiane, additional, Bayas, Antonios, additional, Heesen, Christoph, additional, Kümpfel, Tania, additional, Linker, Ralf, additional, Paul, Friedemann, additional, Stangel, Martin, additional, Tackenberg, Björn, additional, Bergh, Florian Then, additional, Warnke, Clemens, additional, Wiendl, Heinz, additional, Wildemann, Brigitte, additional, Zettl, Uwe, additional, Ziemann, Ulf, additional, Tumani, Hayrettin, additional, Gold, Ralf, additional, Grummel, Verena, additional, Hemmer, Bernhard, additional, Knier, Benjamin, additional, Lill, Christina M., additional, Luessi, Felix, additional, Dardiotis, Efthimios, additional, Agliardi, Cristina, additional, Barizzone, Nadia, additional, Mascia, Elisabetta, additional, Bernardinelli, Luisa, additional, Comi, Giancarlo, additional, Cusi, Daniele, additional, Esposito, Federica, additional, Ferrè, Laura, additional, Comi, Cristoforo, additional, Galimberti, Daniela, additional, Leone, Maurizio A., additional, Sorosina, Melissa, additional, Mescheriakova, Julia, additional, Hintzen, Rogier, additional, van Duijn, Cornelia, additional, Teunissen, Charlotte E., additional, Bos, Steffan D., additional, Myhr, Kjell-Morten, additional, Celius, Elisabeth G., additional, Lie, Benedicte A., additional, Spurkland, Anne, additional, Comabella, Manuel, additional, Montalban, Xavier, additional, Alfredsson, Lars, additional, Stridh, Pernilla, additional, Hillert, Jan, additional, Jagodic, Maja, additional, Piehl, Fredrik, additional, Jelčić, Ilijas, additional, Martin, Roland, additional, Sospedra, Mireia, additional, Ban, Maria, additional, Hawkins, Clive, additional, Hysi, Pirro, additional, Kalra, Seema, additional, Karpe, Fredrik, additional, Khadake, Jyoti, additional, Lachance, Genevieve, additional, Neville, Matthew, additional, Santaniello, Adam, additional, Caillier, Stacy J., additional, Calabresi, Peter A., additional, Cree, Bruce A.C., additional, Cross, Anne, additional, Davis, Mary F., additional, Haines, Jonathan L., additional, de Bakker, Paul I.W., additional, Delgado, Silvia, additional, Dembele, Marieme, additional, Edwards, Keith, additional, Fitzgerald, Kathryn C., additional, Hakonarson, Hakon, additional, Konidari, Ioanna, additional, Lathi, Ellen, additional, Manrique, Clara P., additional, Pericak-Vance, Margaret A., additional, Piccio, Laura, additional, Schaefer, Cathy, additional, McCabe, Cristin, additional, Weiner, Howard, additional, Goldstein, Jacqueline, additional, Olsson, Tomas, additional, Hadjigeorgiou, Georgios, additional, Taylor, Bruce, additional, Tajouri, Lotti, additional, Charlesworth, Jac, additional, Booth, David R., additional, Harbo, Hanne F., additional, Ivinson, Adrian J., additional, Hauser, Stephen L., additional, Compston, Alastair, additional, Stewart, Graeme, additional, Zipp, Frauke, additional, Barcellos, Lisa F., additional, Baranzini, Sergio E., additional, Martinelli-Boneschi, Filippo, additional, D’Alfonso, Sandra, additional, Ziegler, Andreas, additional, Oturai, Annette, additional, McCauley, Jacob L., additional, Sawcer, Stephen J., additional, Oksenberg, Jorge R., additional, De Jager, Philip L., additional, Kockum, Ingrid, additional, Hafler, David A., additional, and Cotsapas, Chris, additional

Published
2019
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19. Additional file 1: Table S1. of Dissecting the role of non-coding RNAs in the accumulation of amyloid and tau neuropathologies in Alzheimerâ s disease

Author

Patrick, Ellis, Sathyapriya Rajagopal, Hon-Kit Wong, McCabe, Cristin, Jishu Xu, Tang, Anna, Imboywa, Selina, Schneider, Julie, Pochet, Nathalie, Krichevsky, Anna, Chibnik, Lori, Bennett, David, and Jager, Philip De

Abstract

Demographic information. Table S3. A table of the correlations between each of the pertinent covariates, Study, Age, Sex, NNLS, PMI, RIN, NP, NFT and AD. Figure S1. Behavior of miRNAs implicated in other experiments. Figure S2. Differentially expressed miRNAs and lincRNAs. Figure S3. Validation of RIN association. (DOCX 483 kb)

Published
2017
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20. A multi-omic atlas of the human frontal cortex for aging and Alzheimer’s disease research

Author

De Jager, Philip L., primary, Ma, Yiyi, additional, McCabe, Cristin, additional, Xu, Jishu, additional, Vardarajan, Badri N., additional, Felsky, Daniel, additional, Klein, Hans-Ulrich, additional, White, Charles C., additional, Peters, Mette A., additional, Lodgson, Ben, additional, Nejad, Parham, additional, Tang, Anna, additional, Mangravite, Lara M., additional, Yu, Lei, additional, Gaiteri, Chris, additional, Mostafavi, Sara, additional, Schneider, Julie A., additional, and Bennett, David A., additional

Published
2018
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21. GEMS Project: A Platform to Investigate Multiple Sclerosis Risk

Author

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.

Subjects
Adult, Male, Multiple Sclerosis, Incidence, Environment, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Article, United States, Risk Factors, Humans, Family, Female, Genetic Predisposition to Disease, Longitudinal Studies
Abstract

The Genes and Environment in Multiple Sclerosis project establishes a platform to investigate the events leading to multiple sclerosis (MS) in at-risk individuals. It has recruited 2,632 first-degree relatives from across the USA. Using an integrated genetic and environmental risk score, we identified subjects with twice the MS risk when compared to the average family member, and we report an initial incidence rate in these subjects that is 30 times greater than that of sporadic MS. We discuss the feasibility of large-scale studies of asymptomatic at-risk subjects that leverage modern tools of subject recruitment to execute collaborative projects.

Published
2015

22. Dissecting the role of non-coding RNAs in the accumulation of amyloid and tau neuropathologies in Alzheimer’s disease

Author

Patrick, Ellis, primary, Rajagopal, Sathyapriya, additional, Wong, Hon-Kit Andus, additional, McCabe, Cristin, additional, Xu, Jishu, additional, Tang, Anna, additional, Imboywa, Selina H., additional, Schneider, Julie A., additional, Pochet, Nathalie, additional, Krichevsky, Anna M., additional, Chibnik, Lori B., additional, Bennett, David A., additional, and De Jager, Philip L., additional

Published
2017
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23. Genetic architecture of age-related cognitive decline in African Americans

Author

Raj, Towfique, primary, Chibnik, Lori B., additional, McCabe, Cristin, additional, Wong, Andus, additional, Replogle, Joseph M., additional, Yu, Lei, additional, Gao, Sujuan, additional, Unverzagt, Frederick W., additional, Stranger, Barbara, additional, Murrell, Jill, additional, Barnes, Lisa, additional, Hendrie, Hugh C., additional, Foroud, Tatiana, additional, Krichevsky, Anna, additional, Bennett, David A., additional, Hall, Kathleen S., additional, Evans, Denis A., additional, and De Jager, Philip L., additional

Published
2016
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24. NR1H3 p.Arg415Gln Is Not Associated to Multiple Sclerosis Risk

Author

Antel, Jack, primary, Ban, Maria, additional, Baranzini, Sergio, additional, Barcellos, Lisa, additional, Barizzone, Nadia, additional, Beecham, Ashley, additional, Berge, Tone, additional, Bernardinelli, Luisa, additional, Booth, David, additional, Bos, Steffan, additional, Buck, Dorothea, additional, Butkiewicz, Mariusz, additional, Celius, Elisabeth G., additional, Comabella, Manuel, additional, Compston, Alastair, additional, Dedham, Katrina, additional, Cotsapas, Chris, additional, D’ Alfonso, Sandra, additional, De Jager, Phil, additional, Dubois, Benedicte, additional, Duquette, Pierre, additional, Fontaine, Bertrand, additional, Gasperi, Christiane, additional, Gil, Elia, additional, Goris, An, additional, Gourraud, Pierre Antoine, additional, Graetz, Christiane, additional, Gyllenberg, Alexandra, additional, Hadjigeorgiou, Georgios, additional, Hafler, David, additional, Hribko, Deanna, additional, Haines, Jonathan, additional, Harbo, Hanne, additional, Hauser, Stephen, additional, Warto, Shannon, additional, Hawkins, Clive, additional, Hemmer, Bernhard, additional, Henry, Roland, additional, Hintzen, Rogier, additional, Horakova, Dana, additional, Ivinson, Adrian, additional, Howard, Melissa, additional, Jelcic, Ilijas, additional, Kaskow, Belinda, additional, Kira, Jun-Ichi, additional, Kleinova, Pavlina, additional, Kockum, Ingrid, additional, Kucerova, Karolina, additional, Lill, Christina, additional, Luessi, Felix, additional, Malhotra, Sunny, additional, Martin, Roland, additional, Martinelli, Filippo, additional, Matsushita, Takuya, additional, McCabe, Cristin, additional, McCauley, Jacob, additional, Mescheriakkova, Julia, additional, Mitrovic, Mitja, additional, Moen, Stine-Marit, additional, Montalban, Xavier, additional, Muhlau, Mark, additional, Nakmura, Yuri, additional, Oksenberg, Jorge, additional, Olsson, Tomas, additional, Oturai, Annette, additional, Palotie, Aarno, additional, Patsopoulos, Nikolaos, additional, Pavlicova, Jana, additional, Pericak-Vance, Peggy, additional, Piehl, Fredrik, additional, Rebeix, Isabelle, additional, Rioux, John, additional, Saarela, Janna, additional, Sawcer, Stephen, additional, Sellebjerg, Finn, additional, Sondergaard, Helle Bach, additional, Sorensen, Per Soelberg, additional, Sospedra, Mireia, additional, Spurkland, Anne, additional, Stewart, Graeme, additional, Taylor, Bruce, additional, Uitterlinden, Andre, additional, Van Duijn, Cornelia, additional, and Zipp, Frauke, additional

Published
2016
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25. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci

Author

Srivastava, Gyan, Lunnon, Katie, Burgess, Jeremy, Yu, Lei, Ernst, Jason, McCabe, Cristin, Tang, Anna, Raj, Towfique, Replogle, Joseph, Brodeur, Wendy, Gabriel, Stacey, Younkin, Curtis, Zou, Fanggeng, Szyf, Moshe, Meissner, Alexander, Ertekin-Taner, Nilufer, Kellis, Manolis, Mill, Jonathan, De Jager, Philip L., Schalkwyk, Leonard C., Eaton, Matthew Lucas, Eaton, Matthew L., Keenan, Brendan T., Chai, High S., Younkin, Steven G., Epstein, Charles B., Schneider, Julie A., Bernstein, Bradley E., Chibnik, Lori B., Bennett, David A., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Eaton, Matthew Lucas, Ernst, Jason, Meissner, Alexander, and Kellis, Manolis

Subjects
Male, Aging, Genome-wide association study, Neurodegenerative, Alzheimer's Disease, 80 and over, 2.1 Biological and endogenous factors, Psychology, Protein Interaction Maps, Aetiology, Epigenomics, Genetics, Aged, 80 and over, General Neuroscience, Intracellular Signaling Peptides and Proteins, Brain, Adaptor Proteins, Nuclear Proteins, Methylation, Amyloidosis, Middle Aged, 3. Good health, CpG site, Neurological, DNA methylation, Female, Cognitive Sciences, Alzheimer's disease, Ankyrins, and over, Biology, Article, Alzheimer Disease, Acquired Cognitive Impairment, medicine, Humans, Genetic Predisposition to Disease, Gene, Adaptor Proteins, Signal Transducing, Aged, Neurology & Neurosurgery, Tumor Suppressor Proteins, Human Genome, Signal Transducing, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), DNA Methylation, medicine.disease, Brain Disorders, Differentially methylated regions, Dementia, CpG Islands, Carrier Proteins, Genome-Wide Association Study
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., National Institutes of Health (U.S.) (Grant R01 AG036042), National Institutes of Health (U.S.) (Grant R01AG036836), National Institutes of Health (U.S.) (Grant R01 AG17917), National Institutes of Health (U.S.) (Grant R01AG15819), National Institutes of Health (U.S.) (Grant R01 AG032990), National Institutes of Health (U.S.) (Grant R01 AG18023), National Institutes of Health (U.S.) (Grant RC2 AG036547), National Institutes of Health (U.S.) (Grant P30 AG10161), National Institutes of Health (U.S.) (Grant P50 AG016574), National Institutes of Health (U.S.) (Grant U01 ES017155), National Institutes of Health (U.S.) (Grant KL2 RR024151), National Institutes of Health (U.S.) (Grant K25 AG041906-01)

Published
2014

26. NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies

Author

Ali, Yousuf O., primary, Allen, Hunter M., additional, Yu, Lei, additional, Li-Kroeger, David, additional, Bakhshizadehmahmoudi, Dena, additional, Hatcher, Asante, additional, McCabe, Cristin, additional, Xu, Jishu, additional, Bjorklund, Nicole, additional, Taglialatela, Giulio, additional, Bennett, David A., additional, De Jager, Philip L., additional, Shulman, Joshua M., additional, Bellen, Hugo J., additional, and Lu, Hui-Chen, additional

Published
2016
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27. Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2transcripts under balancing selection

Author

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

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 ERAP2locus, 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 ERAP2expression caused by nonsense-mediated decay, while the minor haplotype, known to increase Crohn's disease risk, is associated with high ERAP2expression. 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.

Published
2018
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28. Cellular communities reveal trajectories of brain ageing and Alzheimer's disease.

Author

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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