Search

Your search keyword '"Raybould, Rachel"' showing total 33 results
Start Over Author "Raybould, Rachel"
33 results on '"Raybould, Rachel"'

1. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Author

Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen GJ, Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny J, Dols-Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W, Berr, Claudine, Bis, Joshua C, Boland, Anne, Bossù, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, J Nicholas, Daniele, Antonio, Dartigues, Jean-François, Debette, Stéphanie, Deleuze, Jean-François, Denning, Nicola, DeStefano, Anita L, Farrer, Lindsay A, Fernández, Maria Victoria, Fox, Nick C, Galimberti, Daniela, Genin, Emmanuelle, Gille, Johan JP, Le Guen, Yann, Guerreiro, Rita, Haines, Jonathan L, Holmes, Clive, Ikram, M Arfan, Ikram, M Kamran, Jansen, Iris E, Kraaij, Robert, Lathrop, Marc, Lemstra, Afina W, Lleó, Alberto, Luckcuck, Lauren, Mannens, Marcel MAM, Marshall, Rachel, Martin, Eden R, Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O, Morgan, Kevin, Myers, Richard M, Nacmias, Benedetta, Naj, Adam C, Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A, Raybould, Rachel, Redon, Richard, Reinders, Marcel JT, Richard, Anne-Claire, Riedel-Heller, Steffi G, Rivadeneira, Fernando, Rousseau, Stéphane, Ryan, Natalie S, Saad, Salha, Sanchez-Juan, Pascual, Schellenberg, Gerard D, Scheltens, Philip, Schott, Jonathan M, Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik A, Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccolo’, Tijms, Betty, Uitterlinden, André G, van der Lee, Sven J, Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimon, Jordi, van Swieten, John C, Greicius, Michael D, Yokoyama, Jennifer S, Cruchaga, Carlos, Hardy, John, and Ramirez, Alfredo

Subjects
Biological Sciences, Genetics, Dementia, Alzheimer's Disease, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Prevention, Acquired Cognitive Impairment, Neurodegenerative, Aging, Clinical Research, Biotechnology, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Adenosine Triphosphatases, Alzheimer Disease, ATP Binding Cassette Transporter 1, Genome-Wide Association Study, Risk Factors, Exosomes, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

Published
2022

2. Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

Kunkle, Brian W, Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C, Damotte, Vincent, Naj, Adam C, Boland, Anne, Vronskaya, Maria, van der Lee, Sven J, Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R, Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L, Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B, Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N, Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W, Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L, Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V, Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C, Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T, Adams, Hieab H, Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A, Dombroski, Beth A, Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B, Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S, Meslage, Stéphane, Kornhuber, Johannes, White, Charles C, Song, Yuenjoo, Barber, Robert C, Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M, Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L Adrienne, Albert, Marilyn S, De Deyn, Peter P, Gu, Wei, Himali, Jayanadra J, Beekly, Duane, Squassina, Alessio, Hartmann, Annette M, Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E, Doody, Rachelle S, Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J, and Benito, Yolanda A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Alzheimer Disease Genetics Consortium, European Alzheimer’s Disease Initiative, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology, Genetics
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

3. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

Kunkle, Brian W, Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C, Damotte, Vincent, Naj, Adam C, Boland, Anne, Vronskaya, Maria, van der Lee, Sven J, Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R, Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L, Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B, Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N, Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W, Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L, Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V, Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C, Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T, Adams, Hieab H, Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A, Dombroski, Beth A, Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B, Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S, Meslage, Stéphane, Kornhuber, Johannes, White, Charles C, Song, Yuenjoo, Barber, Robert C, Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M, Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L Adrienne, Albert, Marilyn S, De Deyn, Peter P, Gu, Wei, Himali, Jayanadra J, Beekly, Duane, Squassina, Alessio, Hartmann, Annette M, Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E, Doody, Rachelle S, Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J, and Benito, Yolanda A

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Neurodegenerative, Dementia, Alzheimer's Disease, Aging, Prevention, Brain Disorders, Neurosciences, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Neurological, Aged, Alzheimer Disease, Amyloid beta-Peptides, Case-Control Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Haplotypes, Humans, Immunity, Lipid Metabolism, Lipids, Male, tau Proteins, Alzheimer Disease Genetics Consortium (ADGC), European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Published
2019

4. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Author

Sims, Rebecca, van der Lee, Sven J, Naj, Adam C, Bellenguez, Céline, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W, Boland, Anne, Raybould, Rachel, Bis, Joshua C, Martin, Eden R, Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B, Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R, Olaso, Robert, Hoffmann, Per, Grove, Megan L, Vardarajan, Badri N, Hiltunen, Mikko, Nöthen, Markus M, White, Charles C, Hamilton-Nelson, Kara L, Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W, Dulary, Cécile, Herms, Stefan, Smith, Albert V, Funk, Cory C, Derbois, Céline, Forstner, Andreas J, Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L, Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A, Qu, Liming, Sánchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J, Zhao, Yi, Garcia, Florentino Sanchez, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa, Mosley, Thomas H, Dombroski, Beth, Wallon, David, Lupton, Michelle K, Dupuis, Josée, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B, Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D, Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H, Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L Adrienne, Price, Nathan D, Hannequin, Didier, Frank-García, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S, Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E, Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K, Pasquier, Florence, and Boccardi, Virginia

Subjects
ARUK Consortium, GERAD/PERADES, CHARGE, ADGC, EADI, Microglia, Humans, Alzheimer Disease, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Membrane Glycoproteins, Receptors, Immunologic, Odds Ratio, Case-Control Studies, Gene Expression Profiling, Amino Acid Sequence, Sequence Homology, Amino Acid, Gene Frequency, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Phospholipase C gamma, Immunity, Innate, Protein Interaction Maps, Exome, Neurodegenerative, Brain Disorders, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Alzheimer's Disease, Aging, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Published
2017

6. Human papillomavirus integration : the mechanism(s) behind the high-risk associated with this event and cervical disease progression

Author

Raybould, Rachel

Subjects
616.99, RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Abstract

Cervical cancer is the second most common cancer among women worldwide. Infection with Human Papillomavirus (HPV) is essential but not the only contributing factor in cervical cancer development. HPV integration is reported to be present in over 80% of cervical cancers and disruption of HPV genome through integration leads to high levels of HPV oncogene expression. DNA damage and repair pathways are thought to induce HPV integration since HPV is detected at fragile sites in the human genome. There is controversy as to whether integration is an early or late event in cervical oncogenesis and there are no published studies to date that have investigated HPV integration using sensitive, DNA based, techniques at the nucleotide level in cervical precancers. This study aimed to test the hypothesis that integration is an early event in cervical neoplasia and episomal loss causes malignant transformation through transcription of integrated HPV. Also, this study served to pilot whether HPV integration can predict high-grade cervical disease in women with cytological abnormalities with an aim to improve current cervical screening methods. Assays to detect integration and E2 as a marker of episomal state were developed for HPV16, HPV18 and HPV45 and applied to cervical smears and biopsies from women with varying disease grades. The data presented in this thesis highlight that integration may not be essential for cervical cancer progression and different modes of disease progression may exist between young women and older women. Integration was detected at chromosome fragile sites but was more prevalent at SINE or LINE repeat elements; this implies a role for retroelements in the mechanism of integration. Finally, the data here suggest that integration induces a unique selective process in each individual and clonal selection may arise due to altered HPV oncogene expression and/or disruption to human gene expression.

Published
2013

11. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease

Author

Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen G.J., Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny J., Dols-Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W., Berr, Claudine, Bis, Joshua C., Boland, Anne, Bossù, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, J. Nicholas, Daniele, Antonio, Dartigues, Jean-François, Debette, Stéphanie, Deleuze, Jean-François, Denning, Nicola, DeStefano, Anita L, Farrer, Lindsay A., Fernandez, Maria Victoria, Fox, Nick C., Galimberti, Daniela, Genin, Emmanuelle, Gille, Hans, Guen, Yann Le, Guerreiro, Rita, Haines, Jonathan L., Holmes, Clive, Ikram, M. Arfan, Ikram, M. Kamran, Jansen, Iris E., Kraaij, Robert, Lathrop, Marc, Lemstra, Afina W., Lleó, Alberto, Luckcuck, Lauren, Mannens, Marcel M. A. M., Marshall, Rachel, Martin, Eden R, Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O., Morgan, Kevin, Myers, Richard M., Nacmias, Benedetta, Naj, Adam C, Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A., Raybould, Rachel, Redon, Richard, Reinders, Marcel J.T., Richard, Anne-Claire, Riedel-Heller, Steffi G, Rivadeneira, Fernando, Rousseau, Stéphane, Ryan, Natalie S., Saad, Salha, Sanchez-Juan, Pascual, Schellenberg, Gerard D., Scheltens, Philip, Schott, Jonathan M., Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik, Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccólo, Tijms, Betty, Uitterlinden, André G, van der Lee, Sven J., de Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimon, Jordi, van Swieten, John C., Greicius, Michael D., Yokoyama, Jennifer S., Cruchaga, Carlos, Hardy, John, Ramirez, Alfredo, Mead, Simon, van der Flier, Wiesje M., van Duijn, Cornelia M, Williams, Julie, Nicolas, Gaël, Bellenguez, Céline, and Lambert, Jean-Charles

Subjects
Genetics, symbols.namesake, TREM2, SORL1, Mendelian inheritance, symbols, Disease, Allele, Biology, Genome, Gene, Exome sequencing
Abstract

Background With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimer’s Disease (AD), reaching odds ratios comparable with the APOE-e4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenize and analyze these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analyzed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritized using REVEL. Result We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion With our newly developed homogenization methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuroinflammatory processes in AD pathophysiology.

Published
2020

12. Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder

Author

Williams, Nigel M., Green, Elaine K., Macgregor, Stuart, Dwyer, Sarah, Norton, Nadine, Williams, Hywel, Raybould, Rachel, Grozeva, Detelina, Hamshere, Marian, Zammit, Stanley, Jones, Lisa, Cardno, Alastair, Kirov, George, Jones, Ian, O'Donovan, Michael C., Owen, Michael J., and Craddock, Nick

Subjects
Bipolar disorder -- Genetic aspects, Bipolar disorder -- Research, Schizophrenia -- Genetic aspects, Schizophrenia -- Research, Genetic variation -- Research, Health, Psychology and mental health
Published
2006

13. Operation of the schizophrenia susceptibility gene, Neuregulin 1, across traditional diagnostic boundaries to increase risk for Bipolar Disorder

Author

Green, Elaine K., Raybould, Rachel, Macgregor, Stuart, Gordon-Smith, Katherine, Heron, Jess, Hyde, Sally, Grozeva, Detelina, Hamshere, Marian, Williams, Nigel, Owen, Michael J., OEDonovan, Michael C., Jones, Lisa, Jones, Ian, Kirov, George, and Craddock, Nick

Subjects
Genes -- Complications and side effects, Genes -- Research, Bipolar disorder -- Causes of, Bipolar disorder -- Research, Bipolar disorder -- Genetic aspects, Health, Psychology and mental health
Published
2005

14. Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt-Jakob disease

Author

Dabin, Luke, primary, Guntoro, Fernando, additional, Campbell, Tracy, additional, Bélicard, Tony, additional, Smith, Adam R., additional, Smith, Rebecca G., additional, Raybould, Rachel, additional, Schott, Jonathan M., additional, Lunnon, Katie, additional, Sarkies, Peter, additional, Collinge, John, additional, Mead, Simon, additional, and Viré, Emmanuelle, additional

Published
2020
Full Text
View/download PDF

16. Exome sequencing identifies rare damaging variants in ATP8B4and ABCA1as risk factors for Alzheimer’s disease

Author

Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen G. J., Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny J., Dols-Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W., Berr, Claudine, Bis, Joshua C., Boland, Anne, Bossù, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, J. Nicholas, Daniele, Antonio, Dartigues, Jean-François, Debette, Stéphanie, Deleuze, Jean-François, Denning, Nicola, DeStefano, Anita L., Farrer, Lindsay A., Fernández, Maria Victoria, Fox, Nick C., Galimberti, Daniela, Genin, Emmanuelle, Gille, Johan J. P., Le Guen, Yann, Guerreiro, Rita, Haines, Jonathan L., Holmes, Clive, Ikram, M. Arfan, Ikram, M. Kamran, Jansen, Iris E., Kraaij, Robert, Lathrop, Marc, Lemstra, Afina W., Lleó, Alberto, Luckcuck, Lauren, Mannens, Marcel M. A. M., Marshall, Rachel, Martin, Eden R., Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O., Morgan, Kevin, Myers, Richard M., Nacmias, Benedetta, Naj, Adam C., Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A., Raybould, Rachel, Redon, Richard, Reinders, Marcel J. T., Richard, Anne-Claire, Riedel-Heller, Steffi G., Rivadeneira, Fernando, Rousseau, Stéphane, Ryan, Natalie S., Saad, Salha, Sanchez-Juan, Pascual, Schellenberg, Gerard D., Scheltens, Philip, Schott, Jonathan M., Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik A., Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccolo’, Tijms, Betty, Uitterlinden, André G., van der Lee, Sven J., Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimon, Jordi, van Swieten, John C., Greicius, Michael D., Yokoyama, Jennifer S., Cruchaga, Carlos, Hardy, John, Ramirez, Alfredo, Mead, Simon, van der Flier, Wiesje M., van Duijn, Cornelia M., Williams, Julie, Nicolas, Gaël, Bellenguez, Céline, and Lambert, Jean-Charles

Abstract

Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4and ABCA1with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1and ACEhighlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

Published
2022
Full Text
View/download PDF

17. P2‐112: NEXT GENERATION EXOME SEQUENCING IN A LARGE SAMPLE OF ALZHEIMER'S PATIENTS

Author

Grozeva, Detelina, primary, Frizzati, Aura, additional, Sims, Rebecca, additional, Morgan, Taniesha, additional, Raybould, Rachel, additional, Rees, Elliott, additional, Majounie, Elisa, additional, Denning, Nicola, additional, Meggy, Alun, additional, Marshall, Rachel, additional, Beaumont, Bartholomew, additional, Nash, William, additional, Davies, Chloe, additional, Morgan, Joanne, additional, Leonenko, Ganna, additional, Menzies, Georgina E., additional, Badarinarayan, Nandini, additional, Escott-Price, Valentina, additional, and Williams, Julie, additional

Published
2018
Full Text
View/download PDF

19. Periodontitis and Cognitive Decline in Alzheimer’s Disease

Author

Ide, Mark, primary, Harris, Marina, additional, Stevens, Annette, additional, Sussams, Rebecca, additional, Hopkins, Viv, additional, Culliford, David, additional, Fuller, James, additional, Ibbett, Paul, additional, Raybould, Rachel, additional, Thomas, Rhodri, additional, Puenter, Ursula, additional, Teeling, Jessica, additional, Perry, V. Hugh, additional, and Holmes, Clive, additional

Published
2016
Full Text
View/download PDF

20. NEXT GENERATION EXOME SEQUENCING IN A LARGE SAMPLE OF ALZHEIMER’S PATIENTS

Author

Grozeva, Detelina, Frizzati, Aura, Sims, Rebecca, Morgan, Taniesha, Raybould, Rachel, Rees, Elliott, Majounie, Elisa, Denning, Nicola, Meggy, Alun, Marshall, Rachel, Beaumont, Bartholomew, Nash, William, Davies, Chloe, Morgan, Joanne, Leonenko, Ganna, Menzies, Georgina E., Badarinarayan, Nandini, Escott-Price, Valentina, and Williams, Julie

Published
2018
Full Text
View/download PDF

24. P2RX7: A bipolar and unipolar disorder candidate susceptibility gene?

Author

Green, Elaine K., primary, Grozeva, Detelina, additional, Raybould, Rachel, additional, Elvidge, Gareth, additional, Macgregor, Stuart, additional, Craig, Ian, additional, Farmer, Anne, additional, McGuffin, Peter, additional, Forty, Liz, additional, Jones, Lisa, additional, Jones, Ian, additional, O'Donovan, Mick C., additional, Owen, Mike J., additional, Kirov, George, additional, and Craddock, Nick, additional

Published
2009
Full Text
View/download PDF

26. Bipolar disorder and polymorphisms in the dysbindin gene (DTNBP1)

Author

Raybould, Rachel, primary, Green, Elaine K., additional, MacGregor, Stuart, additional, Gordon-Smith, Katherine, additional, Heron, Jess, additional, Hyde, Sally, additional, Caesar, Sian, additional, Nikolov, Ivan, additional, Williams, Nigel, additional, Jones, Lisa, additional, O’Donovan, Michael C., additional, Owen, Michael J., additional, Jones, Ian, additional, Kirov, George, additional, and Craddock, Nick, additional

Published
2005
Full Text
View/download PDF

27. Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease

Author

Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W., Boland, Anne, Raybould, Rachel, Bis, Josha C., Martin, Eden R., Grenier-Boley, Benjamin, Medway, Christopher, Brown, Kristelle, Braae, Anne, Lord, Jenny, Turton, James, Barber, Imelda S., Brookes, Keeley, and Morgan, Kevin

Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

28. Human Papillomavirus integration:\ud The mechanism(s) behind the high-risk associated with this event and cervical disease progression

Author

Raybould, Rachel

Subjects
RC0254
Abstract

Cervical cancer is the second most common cancer among women worldwide. Infection with Human Papillomavirus (HPV) is essential but not the only contributing factor in cervical cancer development. HPV integration is reported to be present in over 80% of cervical cancers and disruption of HPV genome through integration leads to high levels of HPV oncogene expression. DNA damage and repair pathways are thought to induce HPV integration since HPV is detected at fragile sites in the human genome. There is controversy as to whether integration is an early or late event in cervical oncogenesis and there are no published studies to date that have investigated HPV integration using sensitive, DNA based, techniques at the nucleotide level in cervical precancers. This study aimed to test the hypothesis that integration is an early event in cervical neoplasia and episomal loss causes malignant transformation through transcription of integrated HPV. Also, this study served to pilot whether HPV integration can predict high-grade cervical disease in women with cytological abnormalities with an aim to improve current cervical screening methods. Assays to detect integration and E2 as a marker of episomal state were developed for HPV16, HPV18 and HPV45 and applied to cervical smears and biopsies from women with varying disease grades. The data presented in this thesis highlight that integration may not be essential for cervical cancer progression and different modes of disease progression may exist between young women and older women. Integration was detected at chromosome fragile sites but was more prevalent at SINE or LINE repeat elements; this implies a role for retroelements in the mechanism of integration. Finally, the data here suggest that integration induces a unique selective process in each individual and clonal selection may arise due to altered HPV oncogene expression and/or disruption to human gene expression.

29. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author

Sims, Rebecca, Van Der Lee, Sven J, Naj, Adam C, Bellenguez, Céline, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W, Boland, Anne, Raybould, Rachel, Bis, Joshua C, Martin, Eden R, Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B, Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R, Olaso, Robert, Hoffmann, Per, Grove, Megan L, Vardarajan, Badri N, Hiltunen, Mikko, Nöthen, Markus M, White, Charles C, Hamilton-Nelson, Kara L, Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W, Dulary, Cécile, Herms, Stefan, Smith, Albert V, Funk, Cory C, Derbois, Céline, Forstner, Andreas J, Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L, Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A, Qu, Liming, Sánchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J, Zhao, Yi, Garcia, Florentino Sanchez, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa, Mosley, Thomas H, Dombroski, Beth, Wallon, David, Lupton, Michelle K, Dupuis, Josée, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B, Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D, Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H, Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L Adrienne, Price, Nathan D, Hannequin, Didier, Frank-García, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S, Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E, Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K, Pasquier, Florence, Boccardi, Virginia, Henández, Isabel, Barber, Robert C, Scherer, Martin, Tarraga, Lluis, Adams, Perrie M, Leber, Markus, Chen, Yuning, Albert, Marilyn S, Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S, Spalletta, Gianfranco, Longstreth, WT, Fairchild, Thomas J, Bossù, Paola, Lopez, Oscar L, Frosch, Matthew P, Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M, Jessen, Frank, Li, Shuo, Kamboh, M Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J, Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Fairén, Mònica Díez, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T, Lord, Jenny, Turton, James, Hartmann, Annette M, Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleó, Alberto, Fortea, Juan, Blesa, Rafael, Barber, Imelda S, Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C, Hardy, John, ARUK Consortium, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Diaz, Carolina Ceballos, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A, Faber, Kelley M, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Gilbert, John R, Graff-Radford, Neill R, Green, Robert C, Growdon, John H, Hamilton, Ronald L, Harrell, Lindy E, Honig, Lawrence S, Huentelman, Matthew J, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A, Kim, Ronald, Kowall, Neil W, Kramer, Joel H, LaFerla, Frank M, Lah, James J, Leverenz, James B, Levey, Allan I, Li, Ge, Lieberman, Andrew P, Lunetta, Kathryn L, Lyketsos, Constantine G, Marson, Daniel C, Martiniuk, Frank, Mash, Deborah C, Masliah, Eliezer, McCormick, Wayne C, McCurry, Susan M, McDavid, Andrew N, McKee, Ann C, Mesulam, Marsel, Miller, Bruce L, Miller, Carol A, Miller, Joshua W, Morris, John C, Murrell, Jill R, Myers, Amanda J, O'Bryant, Sid, Olichney, John M, Pankratz, Vernon S, Parisi, Joseph E, Paulson, Henry L, Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W, Potter, Huntington, Quinn, Joseph F, Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M, Roberson, Erik D, Rogaeva, Ekaterina, Rosen, Howard J, Rosenberg, Roger N, Sager, Mark A, Saykin, Andrew J, Schneider, Julie A, Schneider, Lon S, Seeley, William W, Smith, Amanda G, Sonnen, Joshua A, Spina, Salvatore, Stern, Robert A, Swerdlow, Russell H, Tanzi, Rudolph E, Thornton-Wells, Tricia A, Trojanowski, John Q, Troncoso, Juan C, Van Deerlin, Vivianna M, Van Eldik, Linda J, Vinters, Harry V, Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A, Wilhelmsen, Kirk C, Williamson, Jennifer, Wingo, Thomas S, Woltjer, Randall L, Wright, Clinton B, Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P, Fernadez, Carmen Muñoz, Benito, Yoland Aladro, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stählbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J, Keene, C Dirk, Tschanz, JoAnn, Fitzpatrick, Annette L, Kukull, Walter A, Norton, Maria, Aspelund, Thor, Larson, Eric B, Munger, Ron, Rotter, Jerome I, Lipton, Richard B, Bullido, María J, Hofman, Albert, Montine, Thomas J, Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C, Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M, Gallo, Maura, O'Donnell, Christopher J, Reisch, Joan S, Bruni, Amalia Cecilia, Royall, Donald R, Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W, Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R, Daniele, Antonio, Wu, Chuang-Kuo, GERAD/PERADES, CHARGE, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C, Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E, Collinge, John, Mann, David, Tsolaki, Magda, Clarimón, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C, Owen, Michael J, Behrens, Timothy W, Mead, Simon, Goate, Alison M, Uitterlinden, Andre G, Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A, Powell, John, Golde, Todd E, Graff, Caroline, De Jager, Philip L, Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M, Passmore, Peter, Younkin, Steven G, Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W, Dartigues, Jean-François, DeStefano, Anita L, Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A, Van Broeckhoven, Christine, Ikram, M Arfan, Jones, Lesley, Haines, Jonathan L, Tzourio, Christophe, Launer, Lenore J, Escott-Price, Valentina, Mayeux, Richard, Deleuze, Jean-François, Amin, Najaf, Holmans, Peter A, Pericak-Vance, Margaret A, Amouyel, Philippe, Van Duijn, Cornelia M, Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, and Schellenberg, Gerard D

Subjects
Membrane Glycoproteins, Genotype, Sequence Homology, Amino Acid, Phospholipase C gamma, Gene Expression Profiling, Polymorphism, Single Nucleotide, Immunity, Innate, Linkage Disequilibrium, 3. Good health, Gene Frequency, Alzheimer Disease, Case-Control Studies, Odds Ratio, Humans, Exome, Genetic Predisposition to Disease, Amino Acid Sequence, Microglia, Protein Interaction Maps, Receptors, Immunologic, Adaptor Proteins, Signal Transducing
Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

30. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimers Disease

Author

Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen, Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny, Dols-Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary, Berr, Claudine, Bis, Joshua, Boland, Anne, Bossu, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, Jesse Nicholas, Daniele, Antonio, Dartigues, Jean-Francois, Debette, Stephanie, Deleuze, Jean-Francois, Denning, Nicola, Destefano, Anita, Farrer, Lindsay, Fernandez, Maria-Victoria, Fox, Nick, Galimberti, Daniela, Genin, Emmanuelle, Gille, Johan JP, Le Guen, Yann, Guerreiro, Rita, Haines, Jonathan, Holmes, Clive, Ikram, M. Arfan, Ikram, M. Kamran, Jansen, Iris E., Kraaij, Robert, Lathrop, Mark, Lemstra, Afina W., Lleo, Alberto, Luckcuck, Lauren, Mannens, Marcel M.A.M., Marschall, Rachel, Martin, Eden, Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel, Morgan, Kevin, Myers, Richard M., Nacmias, Benedetta, Naj, Adam, Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret, Raybould, Rachel, Redon, Richard, Reinders, Marcel J.T., Richard, Anne-Claire, Riedel-Heller, Steffi, Rivadeneira, Fernando, Rousseau, Stephane, Ryan, Natalie, Saad, Salha, Sanchez-Juan, Pascual, Schellenberg, Gerard, Scheltens, Philip, Schott, Jonathan M., Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik A, Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccolo, Tijms, Betty, Uitterlinden, Andre, van der Lee, Sven, Wagner, Michael, Wallon, David, Wang, Li San, Zarea, Aline, Clarimon, Jordi, van Swieten, John, Greicius, Michael D., Yokoyama, Jennifer S., Cruchaga, Carlos, Hardy, John, Ramirez, Alfredo, Mead, Simon H, van der Flier, Wiesje, van Duijn, Cornelia, Williams, Julie, Nicolas, Gael, Bellenguez, Celine, and Lambert, Jean-Charles

Abstract

The genetic component of Alzheimer’s disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals —16,036 AD cases and 16,522 controls— in a two-stage analysis. Next to known genes TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Next to these genes, the rare variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential driver genes in AD-GWAS loci. Rare damaging variants in these genes, and in particular loss-of-function variants, have a large effect on AD-risk, and they are enriched in early onset AD cases. The newly identified AD-associated genes provide additional evidence for a major role for APP-processing, Aβ-aggregation, lipid metabolism and microglial function in AD.

31. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author

Taylor, Sarah, Craig, David, Qu, Liming, Haines, Jonathan L., Morgan, Taniesha, Sager, Mark A., Jun, Gyungah, Beiser, Alexa S., St George-Hyslop, Peter, Levey, Allan I., Vellas, Bruno, Collinge, John, Himali, Jayanadra J., Katz, Mindy J., Frank-García, Ana, Thonberg, Hakan, Grenier-Boley, Benjamin, Emilsson, Valur, Chouraki, Vincent, Jarvik, Gail P., Rotter, Jerome I., Nacmias, Benedetta, Chapman, Jade, Coto, Eliecer, Eiriksdottir, Gudny, Burgess, Jeremy D., Tsolaki, Magda, Saykin, Andrew J., Clarimón, Jordi, Hartmann, Annette M., Beekly, Duane, Peters, Oliver, Fairén, Mònica Díez, Brayne, Carol, Bras, Jose, Zhao, Yi, Riemenschneider, Matthias, Corcoran, Chris, Norton, Maria, Ikram, M Arfan, Gudnason, Vilmundur, Wallon, David, Serpente, Maria, Septier, Gislain, Atwood, Craig S., Yu, Chang-En, Sorbi, Sandro, Carlsson, Cynthia M., McCormick, Wayne C., Urbano, Maria, Galasko, Douglas R., Potter, Huntington, Raj, Ashok, Dufouil, Carole, Reisberg, Barry, Braae, Anne, Fratiglioni, Laura, Forsell, Charlotte, Shaw, Christopher E., Pastor, Pau, Jin, Lee-Way, Carrasquillo, Minerva M., Epelbaum, Jacques, Psaty, Bruce M., McDavid, Andrew N., Lilius, Lena, Ramirez, Alfredo, Berr, Claudine, Green, Robert C., Riedel-Heller, Steffi, Kornhuber, Johannes, Heilmann-Heimbach, Stefanie, Kauwe, John Keoni, Dunstan, Melanie, Miller, Bruce L., McKee, Ann C., Van Broeckhoven, Christine, Harold, Denise, Turton, James, Brookes, Keeley, Owen, Michael J., Brown, Kristelle, Dick, Malcolm, Pilotto, Alberto, Hill, Matt, Carney, Regina M., Thomas, Rhodri, Barber, Imelda S., Gearing, Marla, Brody, Jennifer A, Scarpini, Elio, Graff, Caroline, Pierce, Aimee, Miller, Joshua W., Ruiz, Agustin, Hofman, Albert, Seeley, William W., Hyman, Bradley T., Schellenberg, Gerard D., Campion, Dominique, Patel, Yogen, Welsh-Bohmer, Kathleen A., Martiniuk, Frank, Moreno-Grau, Sonia, Funk, Cory C., Hamilton-Nelson, Kara L., Cribbs, David H., Chakrabarty, Paramita, Keller, Lina, Golde, Todd E., Cao, Chuanhai, Petersen, Ronald C., Evans, Denis A., Leverenz, James B., Frosch, Matthew P., Laferla, Frank M., Pericak-Vance, Margaret A., Woltjer, Randall L., Smith, Albert V., Rogaeva, Ekaterina, Fenoglio, Chiara, Lyketsos, Constantine G., Sussams, Rebecca, Kamboh, M Ilyas, Becker, James T., Mayeux, Richard, Raybould, Rachel, Alvarez, Victoria, Yu, Lei, O'Bryant, Sid, Kim, Ronald, Vinters, Harry V., Aspelund, Thor, Lieberman, Andrew P., Vardarajan, Badri N., Tzourio, Christophe, Tsuang, Debby W., Albert, Marilyn S., Hodges, Angela, Honig, Lawrence S., Sonnen, Joshua A., Hughes, Joseph T., Sacchinelli, Eleonora, Pankratz, Vernon S., Koivisto, Anne Maria, Sleegers, Kristel, Dickson, Dennis W, Vronskaya, Maria, Mead, Simon, Rosenberg, Roger N., Boccardi, Virginia, Graff-Radford, Neill R., Sotolongo-Grau, Oscar, Maier, Wolfgang, Gerrish, Amy, Peskind, Elaine, O'Donnell, Christopher J., Carroll, Steven L., Masullo, Carlo, Garcia, Florentino Sanchez, Sano, Mary, Schmidt, Reinhold, Vonsattel, Jean Paul, Raskind, Murray, McCurry, Susan M., Reitz, Christiane, Dermecourt, Vincent, Hannequin, Didier, Lynch, Aoibhinn, Adams, Perrie M., Gill, Michael, Ahmad, Shahzad, Bacq, Delphine, Stern, Robert A., Burke, James R., Hakonarson, Hakon, Naj, Adam C, Fallon, Kenneth B., De Deyn, Peter P., Masliah, Eliezer, Brundin, Rosemarie, Dubois, Bruno, Schneider, Lon S., Morris, John C., Holmes, Clive, Lunetta, Kathryn L., Duara, Ranjan, Boeve, Bradley F., Larson, Eric B., Fornage, Myriam, Lopez, Oscar L., Lupton, Michelle K., Winslow, Ashley R., Giegling, Ina, Spina, Salvatore, Nöthen, Markus M., Paulson, Henry L., Uphill, James, Blacker, Deborah, Arnold, Steven E., Jakobsdottir, Johanna, Li, Hongdong, Choi, Seung-Hoan, Arcaro, Marina, Dupuis, Josée, Schmidt, Helena, Majounie, Elisa, Powell, John, Pichler, Sabrina, Thornton-Wells, Tricia A., Foroud, Tatiana M., Carlson, Chris S., Jessen, Frank, Boerwinkle, Eric, Younkin, Steven G., Amin, Najaf, Van Deerlin, Vivianna M., Ferris, Steven, Leber, Markus, Thomas, Charlene, Johnston, Janet, Whitehead, Patrice, Dombroski, Beth, Kaye, Jeffrey A., Royall, Donald R., Engelborghs, Sebastien, Spalletta, Gianfranco, Hoffmann, Per, Marshall, Rachel, Orfei, Maria Donata, Bellenguez, Céline, Beach, Thomas G., Haapasalo, Annakaisa, Perry, William, Cecchetti, Roberta, Blesa, Rafael, Bullido, María J., Daniele, Antonio, Fievet, Nathalie, Troncoso, Juan C., Chui, Helena C., Benito, Yoland Aladro, Grove, Megan L., Lord, Jenny, Daniilidou, Makrina, Cairns, Nigel J., Cupples, L Adrienne, Tanzi, Rudolph E., Lipton, Richard B., Galimberti, Daniela, Parisi, Joseph E., Garcia, Melissa E., Ciaramella, Antonio, Mesulam, Marsel, Bigio, Eileen H., Tschanz, Joann, Fernadez, Carmen Muñoz, Giedraitis, Vilmantas, Van Eldik, Linda J., Weintraub, Sandra, Karydas, Anna, Burns, Jeffrey M., Van Duijn, Cornelia M., Farrer, Lindsay A., Derbois, Céline, Combarros, Onofre, Growdon, John H., Satizabal, Claudia L., Escott-Price, Valentina, Ritchie, Karen, Kinhult-Stählbom, Anne, Braddel, Amy, Barnes, Lisa L., Diaz, Carolina Ceballos, Morgan, Kevin, Kramer, Joel H., Ingelsson, Martin, Williams, Julie, Boxer, Adam, Caffarra, Paolo, Aguilar, Miquel, Barral, Sandra, Doody, Rachelle S., Hiltunen, Mikko, Ortega-Cubero, Sara, Concari, Letizia, Passmore, Peter, Huebinger, Ryan M., Sánchez-Juan, Pascual, Fardo, David W., Olichney, John M., Dichgans, Martin, Lambert, Jean-Charles, Gu, Wei, Hardy, John, Gallo, Maura, Lannfelt, Lars, Allen, Mariet, Yang, Qiong, Behrens, Timothy W., Uitterlinden, Andre G., Adams, Hieab H, Henández, Isabel, Levy, Daniel, Cantwell, Laura B., Hulette, Christine M., Lin, Honghuang, Crocco, Elizabeth A., Deleuze, Jean-François, Keene, C Dirk, De Jager, Philip L, Boada, Merce, Soininen, Hilkka, Olaso, Robert, Mayhaus, Manuel, Maletta, Raffaele Giovanni, Graham, Robert R, Trojanowski, John Q., Mancuso, Michelangelo, Mash, Deborah C., Golamaully, Feroze, Naranjo, Maria Candida Deniz, Hamilton, Ronald L., Wang, Xue, Kowall, Neil W., Fox, Nick C., Valladares, Otto, Buxbaum, Joseph D., Bis, Joshua C., Quinn, Joseph F., Martin, Eden R., Brice, Alexis, Cupidi, Chiara, Farlow, Martin R., Wright, Clinton B., Badarinarayan, Nandini, Kukull, Walter A., Price, Nathan D., Hanon, Olivier, Mosley, Thomas H., Chen, Yuning, Proitsi, Petra, Swerdlow, Russell H., Al-Chalabi, Ammar, Williamson, Jennifer, Murrell, Jill R., Panza, Francesco, Boland, Anne, Wolters, Frank J, Rosen, Howard J., Dulary, Cécile, Goate, Alison M., Li, Shuo, Hampel, Harald, Pasquier, Florence, Clark, David G., Schneider, Julie A., Jr, W T Longstreth, Todd, Stephen, Roberson, Erik D., Bird, Thomas D., Lleó, Alberto, Bowen, James D., Reisch, Joan S., Fairchild, Thomas J., Malamon, John, Bosco, Paolo, Garzia, Fabienne, Marson, Daniel C., Reiman, Eric M., Bossù, Paola, Kuzma, Amanda B., Kloszewska, Iwona, Apostolova, Liana G., Carrell, David, Mecocci, Patrizia, Ertekin-Taner, Nilufer, Wilhelmsen, Kirk C., Miller, Carol A., Ghetti, Bernardino, Montine, Thomas J., Kilander, Lena, Jones, Lesley, Lovestone, Simon, Gilbert, John R., Forstner, Andreas J., Wang, Li-San, Smith, Amanda G., Decarli, Charles, Tarraga, Lluis, Seshadri, Sudha, Rivadeneira, Fernando, Crane, Paul K., Helisalmi, Seppo, Squassina, Alessio, Heun, Reinhard, Bonuccelli, Ubaldo, Amouyel, Philippe, Ringman, John M., Destefano, Anita L., Myers, Amanda J., Meggy, Alun, Van Der Lee, Sven J, White, Charles C., Lah, James J., McGuinness, Bernadette, Rubinsztein, David C, Bruni, Amalia Cecilia, Seripa, Davide, Denning, Nicola, Baldwin, Clinton T., Caltagirone, Carlo, Huentelman, Matthew J., Albin, Roger L., Rujescu, Dan, Solfrizzi, Vincenzo, Bennett, David A., Harrell, Lindy E., Herms, Stefan, Faber, Kelley M., Geschwind, Daniel H., Asthana, Sanjay, Beecham, Gary W., Barber, Robert C., Fortea, Juan, Poon, Wayne W., Jian, Xueqiu, Moebus, Susanne, O'Donovan, Michael C., Abner, Erin, Fitzpatrick, Annette L., Mukherjee, Shubhabrata, Wu, Chuang-Kuo, Lawlor, Brian, Guerreiro, Rita, Vandenberghe, Rik, Sims, Rebecca, Kunkle, Brian W., Dartigues, Jean-François, Munger, Ron, Medway, Christopher, Wingo, Thomas S., Li, Ge, Scherer, Martin, and Cruchaga, Carlos

Subjects
3. Good health
Abstract

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P

32. Animal magic.

Author

Hill, Lucy, Parkinson, Stacey, Raybould, Rachel, Blake, Heidi, Ogilvie, Kirstie, and Williamson, Christine

Published
2018

Catalog

Books, media, physical & digital resources
See catalog results