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1. Genome-wide association study identifies risk variants for sporadic Creutzfeldt-Jakob disease in STX6 and GAL3ST1

Author

Anna Poleggi, John Collinge, Carla A. Ibrahim-Verbaas, Jean-Philippe Brandel, Emma Jones, Dimitriadis A, Anna Bartoletti-Stella, James Uphill, Christiane Stehmann, Mok Th, Gerard H. Jansen, Tracy Campbell, Zafar S, Holger Hummerich, van Duijn C, Jiri G. Safar, Ewa Golanska, Martinón-Torres F, Aili Golubjatnikov, Michael B. Coulthart, Zane Jaunmuktane, Beata Sikorska, Giuseppe Matullo, Miguel Calero, Jerome Whitfield, Sabina Capellari, Jean-Louis Laplanche, Kathleen Glisic, Gabor G. Kovacs, Richard Knight, Helen Speedy, Juan Ps, Olga Calero, Jean-Charles Lambert, Stéphane Haïk, Anna Ladogana, Akin Nihat, Stephanie A. Booth, Serena Aneli, Herbert Budka, Pawel P. Liberski, Piero Parchi, Shannon Sarros, Jacqueline M. Linehan, Sebastian Brandner, Maurizio Pocchiari, Ahmed P, Michael D. Geschwind, Fronztek K, Antonio Salas, Inga Zerr, Janis Blevins, Elodie Bouaziz-Amar, Brian S. Appleby, Steven J. Collins, P. Gambetti, Hata Karamujić-Čomić, Adriano Aguzzi, Philippe Amouyel, van der Lee S, Penny Norsworthy, Parmjit S. Jat, Liam Quinn, Emmanuelle Viré, and Simon Mead

Subjects
Genetics, 0303 health sciences, biology, animal diseases, Tau protein, STX6, Single-nucleotide polymorphism, Genome-wide association study, medicine.disease, 3. Good health, Progressive supranuclear palsy, PRNP, nervous system diseases, 03 medical and health sciences, 0302 clinical medicine, medicine, biology.protein, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

Mammalian prions are lethal pathogens composed of fibrillar assemblies of misfolded prion protein. Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the gene that encodes prion protein (PRNP) are strong risk factors for sCJD, but although the condition has heritability similar to other neurodegenerative disorders, no other risk loci have yet been confirmed. By genome-wide association in European ancestry populations, we found three replicated loci (cases n=5208, within PRNP, STX6, and GAL3ST1) and two further unreplicated loci were significant in gene-wide tests (within PDIA4, BMERB1). Exome sequencing in 407 sCJD cases, conditional and transcription analyses suggest that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 and PDIA4 associate with increased expression of the major transcripts in disease-relevant brain regions. Alteration of STX6 expression does not modify prion propagation in a neuroblastoma cell model of mouse prion infection. We went on to analyse the proteins histologically in diseased tissue and examine the effects of risk variants on clinical phenotypes using deep longitudinal clinical cohort data. Risk SNPs in STX6, a protein involved in the intracellular trafficking of proteins and vesicles, are shared with progressive supranuclear palsy, a neurodegenerative disease associated with the misfolded protein tau. We present the first evidence of statistically robust associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism.

Published
2020
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2. Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study

Author

Gabor G. Kovacs, Stephanie A. Booth, Sebastian Brandner, Penny Norsworthy, Anna Ladogana, Akin Nihat, Herbert Budka, Saima Zafar, Helen Speedy, Antonio Salas, Parvin Ahmed, Holger Hummerich, Gerard H. Jansen, Tze How Mok, Michael D. Geschwind, Beata Sikorska, Maurizio Pocchiari, Christiane Stehmann, Sabina Capellari, Jean-Louis Laplanche, Sven J. van der Lee, Emma Jones, Jean-Charles Lambert, Olga Calero, Pierluigi Gambetti, Ewa Golanska, Serena Aneli, Richard Knight, Giuseppe Matullo, Pawel P. Liberski, Athanasios Dimitriadis, Jerome Whitfield, Hata Karamujić-Čomić, Federico Martinón-Torres, Emmanuelle Viré, Jiri G. Safar, Tracy Campbell, Pascual Sánchez-Juan, Katie Glisic, Anna Bartoletti-Stella, Carla A. Ibrahim-Verbaas, Adriano Aguzzi, Anna Poleggi, Aili Golubjatnikov, Karl Frontzek, Jean Phillipe Brandel, Phillipe Amouyel, Parmjit S. Jat, Zane Jaunmuktane, Simon Mead, Steven J. Collins, Inga Zerr, Liam Quinn, Piero Parchi, Janis Blevins, Elodie Bouaziz-Amar, Brian S. Appleby, Shannon Sarros, Jacqueline M. Linehan, Miguel Calero, Michael B. Coulthart, Stéphane Haïk, John Collinge, James Uphill, Cornelia M. van Duijn, Diseases, Network Centre for Biomedical Research in Neurodegenerative, Jones E., Hummerich H., Vire E., Uphill J., Dimitriadis A., Speedy H., Campbell T., Norsworthy P., Quinn L., Whitfield J., Linehan J., Jaunmuktane Z., Brandner S., Jat P., Nihat A., How Mok T., Ahmed P., Collins S., Stehmann C., Sarros S., Kovacs G.G., Geschwind M.D., Golubjatnikov A., Frontzek K., Budka H., Aguzzi A., Karamujic-Comic H., van der Lee S.J., Ibrahim-Verbaas C.A., van Duijn C.M., Sikorska B., Golanska E., Liberski P.P., Calero M., Calero O., Sanchez-Juan P., Salas A., Martinon-Torres F., Bouaziz-Amar E., Haik S., Laplanche J.-L., Brandel J.-P., Amouyel P., Lambert J.-C., Parchi P., Bartoletti-Stella A., Capellari S., Poleggi A., Ladogana A., Pocchiari M., Aneli S., Matullo G., Knight R., Zafar S., Zerr I., Booth S., Coulthart M.B., Jansen G.H., Glisic K., Blevins J., Gambetti P., Safar J., Appleby B., Collinge J., Mead S., Universidad de Cantabria, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Epidemiology

Subjects
0301 basic medicine, epidemiology [Creutzfeldt-Jakob Syndrome], Tau protein, Single-nucleotide polymorphism, Genome-wide association study, diagnosis [Creutzfeldt-Jakob Syndrome], Disease, genetics [Genetic Loci], methods [Genome-Wide Association Study], Polymorphism, Single Nucleotide, Creutzfeldt-Jakob Syndrome, PRNP, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Humans, Genetic Predisposition to Disease, ddc:610, genetics [Genetic Predisposition to Disease], Genotyping, Exome sequencing, Genetics, biology, Odds ratio, genetics [Creutzfeldt-Jakob Syndrome], 030104 developmental biology, Genetic Loci, epidemiology [Genetic Predisposition to Disease], biology.protein, genetics [Polymorphism, Single Nucleotide], Neurology (clinical), 030217 neurology & neurosurgery, Genome-Wide Association Study, Human
Abstract

Background Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. Methods We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. Findings Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17–1·30], p=2·68 × 10 −15; heterozygous model p=1·01 × 10 −135), STX6 (rs3747957; OR 1·16 [1·10–1·22], p=9·74 × 10 −9), and GAL3ST1 (rs2267161; OR 1·18 [1·12–1·25], p=8·60 × 10 −10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. Interpretation We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. Funding Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.

Published
2020
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3. Convergent genetic and expression data implicate immunity in Alzheimer's disease

Author

John R. Gilbert, Simon Lovestone, Diana Zelenika, Walter A. Kukull, Peter Passmore, Chiao-Feng Lin, Nathalie Fievet, Brian W. Kunkle, Dominique Campion, Philip L. De Jager, Adam C. Naj, Kara L. Hamilton-Nelson, Lina Keller, Jean-Charles Lambert, Denise Harold, Paul K. Crane, John Powell, Kathryn L. Lunetta, Paolo Caffarra, Lei Yu, Anthony Bayer, Tricia A. Thornton-Wells, Christiane Reitz, Eric B. Larson, Florentino Sanchez Garcia, Lindsay A. Farrer, Charlene Thomas, Ekaterina Rogaeva, Victoria Alavarez, Alfredo Ramirez, Pascale Barberger-Gateau, Dan Rujescu, Paul Hollingworth, Margaret A. Pericak-Vance, Daniela Galimberti, J. Kornhuber, Alexey Vedernikov, Philippe Amouyel, Peter Holmans, Gianfranco Spalletta, Carole Dufouil, Wolfgang Maier, Patrick G. Kehoe, Florence Pasquier, Lesley Jones, Harald Hampel, Stephen Todd, Valur Emilsson, Pau Pastor, Manuel Mayhaus, Claudine Berr, Seth Love, Michelangelo Mancuso, Mikko Hiltunen, Simon Mead, Hilkka Soininen, Vincent Deramecourt, Bernadette McGuinness, Magda Tsolaki, Jean-François Dartigues, Jordi Clarimón, Marie-Thérèse Bihoreau, Laura Fratiglioni, Duane Beekly, Sabrina Pichler, Caroline Graff, Albert V. Smith, Nick C. Fox, Amy Gerrish, Karen Ritchie, Carlos Cruchaga, John Hardy, Benedetta Nacmias, Maria Candida Deniz Naranjo, Christine Van Broeckhoven, Laura B. Cantwell, Minerva M. Carrasquillo, Richard Mayeux, Karolien Bettens, Vincent Chouraki, Clive Holmes, Thomas H. Mosley, David C. Rubinsztein, Gyungah Jun, Anita L. DeStefano, Lenore J. Launer, Alexander Richards, Jerome I. Rotter, Lars Lannfelt, Annette L. Fitzpatrick, Fanggeng Zou, Joseph D. Buxbaum, Cristina Razquin, Mercè Boada, Najaf Amin, Palmi V. Jonsson, Martin Dichgans, Thomas J. Montine, Yoichiro Kamatani, Debby W. Tsuang, Alexis Brice, Hakon Hakonarson, John Collinge, Albert Hofman, Eden R. Martin, Oscar L. Lopez, Olivier Hanon, Melanie L. Dunstan, Kevin Morgan, Nicola Jones, Cornelia M. van Duijn, Valentina Escott-Price, Vilmundur Gudnason, Susanne Moebus, Peter St George-Hyslop, Michael Conlon O'Donovan, Michael Gill, Tim Becker, Markus M. Nöthen, Sandro Sorbi, Céline Bellenguez, Mike A. Nalls, Martin Ingelsson, Otto Valladares, Kristel Sleegers, Sudha Seshadri, Gerard D. Schellenberg, María J. Bullido, Patrizia Mecocci, Eric Boerwinkle, Michael John Owen, Helena Schmidt, Kristelle Brown, Julie Williams, Renée F.A.G. de Bruijn, Jonathan L. Haines, Mark Lathrop, Maria Del Zompo, Denis A. Evans, Rebecca Sims, Badri N. Vardarajan, John S. K. Kauwe, Luc Letteneur, Agustín Ruiz, David Craig, Steven G. Younkin, Bruce M. Psaty, Ignacio Mateo, Tatiana Foroud, David Wallon, P. Bosco, Alberti Lleò, Amanda J. Myers, Alberto Pilotto, Petra Proitsi, Reinhold Schmidt, Matthew J. Huentelman, David A. Bennett, Onofre Combarros, Kelley Faber, Gudny Eiriksdottir, M. Arfan Ikram, Lluís Tárraga, Francesco Panza, Carla A. Ibrahim-Verbaas, Joshua C. Bis, Li-San Wang, Matthias Riemenschneider, Gary W. Beecham, Alison Goate, Seung Hoan Choi, John Gallacher, Robert Clarke, Didier Hannequin, Deborah Blacker, Frank Jessen, Christophe Tzourio, Tamara B. Harris, Benjamin Grenier-Boley, Paola Bossù, Janet A. Johnston, M. Ilyas Kamboh, Giancarlo Russo, Timothy Stone, Carol Brayne, Eliecer Coto, French National Foundation on Alzheimer’s Disease and Related Disorders, Institut Pasteur, National Institutes of Health (US), Centre National de Genotypage (France), Fédération pour la Recherche sur le Cerveau (France), Erasmus University Rotterdam, Medical Research Council (UK), International Genomics of Alzheimer's Disease Consortium (IGAP), Neurology, and Epidemiology

Subjects
Pathway analysis, Epidemiology, ALIGATOR, Alzheimer's disease, Cholesterol metabolism, Dementia, Endocytosis, Immune response, Neurodegeneration, Ubiquitination, Weighted gene co-expression network analysis, Medizin, Genome-wide association study, genetics [Alzheimer Disease], Gene expression, Genetics, education.field_of_study, Health Policy, Brain, Single Nucleotide, 3. Good health, Psychiatry and Mental Health, Algorithms, Alzheimer Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Developmental Neuroscience, Neurology (clinical), Geriatrics and Gerontology, Cellular and Molecular Neuroscience, Alzheimer’s disease, metabolism [Alzheimer Disease], Population, Genomics, Biology, Aligator, Article, Biological pathway, SDG 3 - Good Health and Well-being, medicine, ddc:610, Polymorphism, education, medicine.disease, Protein ubiquitination, metabolism [Brain], Human medicine
Abstract

© 2015, Elsevier Inc. All rights reserved. Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P =.002-.05). Conclusions: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics., Medical Research Council, Alzheimer’s Research UK, and theWelsh Assembly Government. ADGC and CHARGE were supported by the National Institutes of Health, National Institute on Aging (NIH-NIA). CHARGE was also supported by Erasmus Medical Center and Erasmus University. IGAP was funded by the French National Foundation on Alzheimer’s Disease and Related Disorders, the Centre National de Genotypage and the Institut Pasteur de Lille, Inserm, FRC (Fondation pour la Recherche sur le Cerveau), and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease).

Published
2015
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4. A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

Author

Anais Mounier, James T. Becker, Vincent Chouraki, Robert S. Rogers, P. Amouyel, Florie Demiautte, R. F. A. G. de Bruijn, Richard Mayeux, Annette L. Fitzpatrick, J. C. Bis, J. F. Dartigues, Carla A. Ibrahim-Verbaas, A. Hofman, Christophe Tzourio, Benjamin Grenier-Boley, M. A. Ikram, Mark Lathrop, A.G. Uitterlinden, Oscar L. Lopez, Claudine Berr, Nicole Schupf, M.M.B. Breteler, Christiane Reitz, Annick Alpérovitch, J-C Lambert, C M van Duijn, Susanna Schraen, Luc Buée, Charlotte Delay, and Julien Chapuis

Subjects
Aging, Amyloid beta, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, APP protein, human, White People, Article, Cellular and Molecular Neuroscience, Amyloid beta-Protein Precursor, SDG 3 - Good Health and Well-being, blood [Amyloid beta-Peptides], metabolism [Amyloid beta-Protein Precursor], blood [Aging], medicine, Humans, ddc:610, Senile plaques, Molecular Biology, Gene, Amyloid beta-Peptides, CTXN3 protein, human, HEK 293 cells, Membrane Proteins, amyloid beta-protein (1-40), amyloid beta-protein (1-42), medicine.disease, Peptide Fragments, genetics [European Continental Ancestry Group], genetics [Membrane Proteins], Psychiatry and Mental health, HEK293 Cells, Membrane protein, Biochemistry, genetics [Amyloid beta-Protein Precursor], blood [Peptide Fragments], genetics [Aging], biology.protein, Alzheimer's disease, metabolism [Membrane Proteins], Genome-Wide Association Study
Abstract

Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ 1-40 and Aβ 1 -42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P

Published
2014
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5. The sex-specific associations of the aromatase gene with Alzheimer's disease and its interaction with IL10 in the Epistasis Project

Author

Kristelle Brown, Helen Butler, C M van Duijn, Naomi Hammond, A. D. Smith, Mario Cortina-Borja, Rachel Barber, de Bruijn Rfag., Christopher Medway, Mohammad Arfan Ikram, Gordon K. Wilcock, Eliecer Coto, Ignacio Mateo, Pascual Sánchez-Juan, Onofre Combarros, Patrick G. Kehoe, R. Heun, D J Lehmann, Peter J. Koudstaal, Heike Kölsch, Panagiotis Deloukas, Olivia Belbin, Kevin Morgan, Donald Warden, Michael G Lehmann, Victoria Alvarez, Carla A. Ibrahim-Verbaas, Neurology, Epidemiology, and Radiology & Nuclear Medicine

Subjects
Male, Risk, medicine.medical_specialty, Linkage disequilibrium, Estrogen receptor, Disease, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Aromatase, Gene Frequency, Alzheimer Disease, Internal medicine, Odds Ratio, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Genetics (clinical), Aged, Aged, 80 and over, Sex Characteristics, Case-control study, Epistasis, Genetic, Odds ratio, medicine.disease, Interleukin-10, Endocrinology, Case-Control Studies, biology.protein, Epistasis, Female, Alzheimer's disease
Abstract

Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG = 1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor = 1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.

Published
2014
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6. Intensity of human prion disease surveillance predicts observed disease incidence

Author

Maren Breithaupt, Inga Zerr, Annick Alpérovitch, Robert G. Will, Steven J. Collins, Gerard H. Jansen, Rachel Howley, Marion Simpson, Michael Farrell, Michael Coulthard, Genevieve M Klug, Cornelia M. van Duijn, Handan Wand, Alison Boyd, Colin L. Masters, Jean-Philippe Brandel, Matthew Law, Gabor G. Kovacs, Jan Mackenzie, Herbert Budka, Radoslav Matěj, Carla A. Ibrahim-Verbaas, University of Zurich, Klug, Genevieve M J A, Epidemiology, and Neurology

Subjects
Canada, Pediatrics, medicine.medical_specialty, Population, 10208 Institute of Neuropathology, Surveillance Methods, 610 Medicine & health, Disease, Creutzfeldt-Jakob Syndrome, Prion Diseases, 2738 Psychiatry and Mental Health, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Public health surveillance, Epidemiology, medicine, Humans, Dementia, Public Health Surveillance, Registries, 030212 general & internal medicine, education, Psychiatry, Disease surveillance, education.field_of_study, business.industry, Incidence, Incidence (epidemiology), Australia, medicine.disease, 2746 Surgery, nervous system diseases, 3. Good health, Europe, Psychiatry and Mental health, 2728 Neurology (clinical), Epidemiological Monitoring, 570 Life sciences, biology, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Background Prospective national screening and surveillance programmes serve a range of public health functions. Objectively determining their adequacy and impact on disease may be problematic for rare disorders. We undertook to assess whether objective measures of disease surveillance intensity could be developed for the rare disorder sporadic Creutzfeldt–Jakob disease (CJD) and whether such measures correlate with disease incidence. Method From 10 countries with national human prion disease surveillance centres, the annual number of suspected prion disease cases notified to each national unit (n=17 610), referrals for cerebrospinal fluid (CSF) 14-3-3 protein diagnostic testing (n=28 780) and the number of suspect cases undergoing diagnostic neuropathological examination (n=4885) from 1993 to 2006 were collected. Age and survey year adjusted incidence rate ratios with 95% CIs were estimated using Poisson regression models to assess risk factors for sporadic, non-sporadic and all prion disease cases. Results Age and survey year adjusted analysis showed all three surveillance intensity measures (suspected human prion disease notifications, 14-3-3 protein diagnostic test referrals and neuropathological examinations of suspect cases) significantly predicted the incidence of sporadic CJD, non-sporadic CJD and all prion disease. Conclusions Routine national surveillance methods adjusted as population rates allow objective determination of surveillance intensity, which correlates positively with reported incidence for human prion disease, especially sporadic CJD, largely independent of national context. The predictive relationship between surveillance intensity and disease incidence should facilitate more rapid delineation of aberrations in disease occurrence and assessment of the adequacy of disease monitoring by national registries.

Published
2013
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7. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease

Author

Johanna Jakobsdottir, Sven J van der Lee, Joshua C Bis, Vincent Chouraki, David Li-Kroeger, Shinya Yamamoto, Megan L Grove, Adam Naj, Maria Vronskaya, Jose L Salazar, Anita L DeStefano, Jennifer A Brody, Albert V Smith, Najaf Amin, Rebecca Sims, Carla A Ibrahim-Verbaas, Seung-Hoan Choi, Claudia L Satizabal, Oscar L Lopez, Alexa Beiser, M Arfan Ikram, Melissa E Garcia, Caroline Hayward, Tibor V Varga, Samuli Ripatti, Paul W Franks, Göran Hallmans, Olov Rolandsson, Jan-Håkon Jansson, David J Porteous, Veikko Salomaa, Gudny Eiriksdottir, Kenneth M Rice, Hugo J Bellen, Daniel Levy, Andre G Uitterlinden, Valur Emilsson, Jerome I Rotter, Thor Aspelund, Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, Alzheimer’s Disease Genetic Consortium, Genetic and Environmental Risk in Alzheimer’s Disease consortium, Christopher J O'Donnell, Annette L Fitzpatrick, Lenore J Launer, Albert Hofman, Li-San Wang, Julie Williams, Gerard D Schellenberg, Eric Boerwinkle, Bruce M Psaty, Sudha Seshadri, Joshua M Shulman, Vilmundur Gudnason, Cornelia M van Duijn, Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, VU University medical center, Clinicum, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Department of Public Health, Biostatistics Helsinki, Complex Disease Genetics, and Haines, Jonathan L

Subjects
Male, Apolipoprotein E, Genetic and Environmental Risk in Alzheimer’s Disease consortium, Aging, PROTEIN, Social Sciences, Genome-wide association study, Tropomyosin, Alzheimer's Disease, Cell Signaling, Sociology, Age of Onset, Aetiology, MUTATION, Notch Signaling, Drosophila Melanogaster, Intracellular Signaling Peptides and Proteins, COMMON VARIANTS, Genomics, Phenotypes, Drosophila melanogaster, Neurology, medicine.medical_specialty, Notch, European Continental Ancestry Group, White People, APOLIPOPROTEIN-E, Presenilin, 03 medical and health sciences, Apolipoproteins E, SDG 3 - Good Health and Well-being, Clinical Research, Alzheimer Disease, Genetics, Humans, Rare functional variant, GENOME-WIDE ASSOCIATION, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, Aged, Embryos, Organisms, Correction, Biology and Life Sciences, Odds ratio, Invertebrates, 030104 developmental biology, Endocrinology, Genetic Loci, Mutation, Dementia, Developmental Biology, 0301 basic medicine, Embryology, Cancer Research, Iceland, Neurodegenerative, QH426-470, Amyloid beta-Protein Precursor, Alzheimer’s Disease Genetic Consortium, Consortia, Receptors, Invertebrate Genomics, Medicine and Health Sciences, Drosophila Proteins, 2.1 Biological and endogenous factors, Exome, DROSOPHILA-MELANOGASTER DEVELOPMENT, Genetics (clinical), Receptors, Notch, Neurodegenerative Diseases, Animal Models, Insects, Phenotype, Neurological, Female, Drosophila, Neurovetenskaper, Research Article, Signal Transduction, Arthropoda, UNITED-STATES, Late onset, Biology, Research and Analysis Methods, IDENTIFIES VARIANTS, Model Organisms, Internal medicine, Mental Health and Psychiatry, Acquired Cognitive Impairment, medicine, Animals, Allele, HAPLOTYPE RECONSTRUCTION, Human Genome, Neurosciences, Membrane Proteins, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Cell Biology, Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, Brain Disorders, Animal Genomics, RC0321, 3111 Biomedicine, Age of onset, Genome-Wide Association Study
Abstract

We performed an exome-wide association analysis in 1393 late-onset Alzheimer’s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus, Author Summary Alzheimer’s disease (AD) is the most common cause of dementia in the older adult population. There is substantial evidence for an important genetic contribution to AD risk. While prior work has comprehensively evaluated the contribution of common genetic variants in large population-based cohorts, the role of rare variants remains to be defined. Here, we have used a newer genotyping array to characterize less common variants, including those likely to impact the function of encoded proteins, in a combined cohort of 1393 AD cases and 8141 control subjects without AD. Our results implicate a novel, amino acid-changing variant, P155L, in the TM2D3 gene. This variant was discovered to be more common in the Icelandic population, where it was significantly associated with both increased risk and earlier age of onset of AD. Lastly, in order to examine the potential functional impact of the implicated variant, we performed additional studies in the fruit fly. Our results suggest that P155L causes a loss-of-function in TM2D3, in the context of Notch-Presenilin signal transduction. In sum, we identify a novel, rare TM2D3 variant in association with AD risk and highlight functional connections with AD-relevant biology.

Published
2016
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8. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

Author

Magnus Johannesson, André G. Uitterlinden, Cornelius A. Rietveld, Nicholas J. Timpson, Sarah E. Medland, Tõnu Esko, Beben Benyamin, Ian J. Deary, Sven J. van der Lee, Christiaan de Leeuw, Nicholas G. Martin, Matt McGue, Cornelia M. van Duijn, David C. Liewald, Patrick Turley, Nancy L. Pedersen, Paul Lichtenstein, Jaime Derringer, Frank C. Verhulst, James J. Lee, Carla A. Ibrahim-Verbaas, Dalton Conley, Philipp Koellinger, John M. Starr, Tune H. Pers, Christopher F. Chabris, David Cesarini, David Laibson, Edward L. Glaeser, Najaf Amin, Olga Rostapshova, Maciej Trzaskowski, Juha Karjalainen, Mary E. Ward, Caroline Hayward, Valur Emilsson, Patrik K. E. Magnusson, Henning Tiemeier, Daniel J. Benjamin, Robert Plomin, David J. Porteous, George Davey Smith, Michael B. Miller, Margaret J. Wright, Fernando Rivadeneira, Vincent W. V. Jaddoe, Anna A. E. Vinkhuyzen, William G. Iacono, Lude Franke, Peter M. Visscher, Rudolf S N Fehrmann, Gail Davies, Andrew D. Johnson, Steven Pinker, Riccardo E. Marioni, Blair H. Smith, George McMahon, Danielle Posthuma, Narelle K. Hansell, Human genetics, NCA - Brain mechanisms in health and disease, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Functional Genomics, Complex Trait Genetics, Tinbergen Institute, Amsterdam Neuroscience - Complex Trait Genetics, Rietveld, Cornelius A, Esko, Tõnu, Davies, Gail, Pers, Tune H, Benyamin, Beben, Koellinger, Philipp D, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Entrepreneurship & Innovation (ABS, FEB), Epidemiology, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, and Internal Medicine

Subjects
Male, Multifactorial Inheritance, Cell Adhesion Molecules, Neuronal, LOCI, Social Sciences, Single-nucleotide polymorphism, Genome-wide association study, INTELLIGENCE, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Synaptic Transmission, Corrections, Cognition, Memory, medicine, ACADEMIC-ACHIEVEMENT, Dementia, GWAS, Humans, Learning, Effects of sleep deprivation on cognitive performance, GENOME-WIDE ASSOCIATION, Neural Cell Adhesion Molecules, Genetics, Multidisciplinary, Neuronal Plasticity, proxy-phenotype method, Memoria, COMPONENTS, Calcium-Binding Proteins, medicine.disease, Multiple comparisons problem, Octamer Transcription Factors, Female, SDG 4 - Quality Education
Abstract

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxyphenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. Refereed/Peer-reviewed

Published
2014
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9. O3–01–05: The role of functional genetic variation in Alzheimer's disease: The CHARGE consortium

Author

Vilmundur Gudnason, Eric Boerwinkle, Johanna Jakobsdottir, Cornelia M. van Duijn, Sudha Seshadri, Albert Hofman, Anita L. DeStefano, Lenore J. Launer, Sven J. van der Lee, Mohammad Arfan Ikram, Megan Grove-Gaona, Joshua C. Bis, A. E. Smith, Carla A. Ibrahim-Verbaas, Vincent Chouraki, Annette L. Fitzpatrick, André G. Uitterlinden, and Christopher P. O'Donnell

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genetic variation, Charge (physics), Neurology (clinical), Disease, Geriatrics and Gerontology, Biology
Published
2013
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10. F1–01–02: APOE‐stratified genome‐wide association analysis reveals differential effects by APOE status and potential new risk loci for Alzheimer's disease

Author

Carla A. Ibrahim-Verbaas

Subjects
Genetics, Apolipoprotein E, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genome-Wide Association Analysis, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology, Differential effects
Published
2013
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11. GWAS of 126559 Individuals Identifies Genetic Variants Associated with Educational Attainment

Author

Maria Dimitriou, Klaus Berger, Jian Yang, Nicholas J. Timpson, George Dedoussis, Magnus Johannesson, Igor Rudan, Marisa Loitfelder, Kurt Lohman, Jürgen Wellmann, Osorio Meirelles, Johan G. Eriksson, Cornelia M. van Duijn, Francesco Cucca, Anu Realo, Gérard Waeber, David R. Van Wagoner, Samuli Ripatti, Alan F. Wright, George McMahon, Elizabeth G. Holliday, Lili Milani, Ute Bültmann, Olli T. Raitakari, Behrooz Z. Alizadeh, Reinhold Schmidt, Matthew Kowgier, André G. Uitterlinden, Sutapa Mukherjee, William G. Iacono, Judith M. Vonk, Lude Franke, John M. Starr, Antonio Terracciano, Rudolf Ferhmann, Pamela A. F. Madden, Marika Kaakinen, Helena Schmidt, Dorret I. Boomsma, Harry Campbell, Konstantin Shakhbazov, Lei Yu, Albert Hofman, Tõnu Esko, Cornelius A. Rietveld, Albert V. Smith, Arpana Agrawal, Wouter J. Peyrot, Stefania Bandinelli, David M. Evans, Nicolas W. Martin, Martin F. Elderson, Melissa E. Garcia, Danielle Posthuma, Ozren Polasek, Panos Deloukas, Pedro Marques Vidal, Sang Hong Lee, James F. Wilson, Robert F. Krueger, Paul Lichtenstein, Jan-Emmanuel De Neve, Fernando Rivadeneira, Laura J. Bierut, Sebastian E. Baumeister, Lawrence F. Bielak, Peter M. Visscher, Philipp Koellinger, Thais S. Rizzi, Rodney J. Scott, Mika Kähönen, Marco Masala, Debbie A Lawlor, Yongmei Liu, Ben A. Oostra, Jaime Derringer, Zoltán Kutalik, Carla A. Ibrahim-Verbaas, Toshiko Tanaka, Håkon K. Gjessing, Jae Hoon Sul, Marjo-Riitta Järvelin, Krista Fischer, Erik Ingelsson, David R. Weir, Kati Kristiansson, Thomas Illig, Jorma Viikari, George Davey-Smith, Antti-Pekka Sarin, Matt McGue, Ida Surakka, Andreas Mielck, Ivana Kolcic, Astanand Jugessur, Aldo Rustichini, Sarah E. Medland, Ronny Myhre, Veikko Salomaa, Mina K. Chung, H.-Erich Wichmann, Lynn Cherkas, Peter Lichtner, Michael B. Miller, Peter Vollenweider, Jüri Allik, Henning Tiemeier, Grant W. Montgomery, Eva Reinmaa, Dalton Conley, Adriaan Hofman, Patricia A. Peyser, David Schlessinger, Martin Preisig, Jessica D. Faul, Patrik K. E. Magnusson, David A. Bennett, Erkki Vartiainen, David Laibson, François Bastardot, Niina Eklund, Wolfgang Hoffmann, Terho Lehtimäki, Nicholas D. Hastie, John P. Rice, Rolf Holle, Antti Latvala, Guoný Eiríksdóttir, Luigi Ferrucci, Jennifer A. Smith, Christian Gieger, Veronique Vitart, Gail Davies, Sara Hägg, Juha Karjalainen, Matthijs J. H. M. van der Loos, Bo Jacobsson, Lydia Quaye, John Barnard, Beate St Pourcain, Jouke-Jan Hottenga, Daniel S. Evans, Jonathan P. Beauchamp, Tamara B. Harris, Ian J. Deary, Jari Lahti, Peng Lin, Markus Perola, Henry Völzke, Lenore J. Launer, David C. Liewald, Brenda W.J.H. Penninx, David Cesarini, Najaf Amin, Dale R. Nyholt, Roy Thurik, Aarno Palotie, Patrick J. F. Groenen, Elisabeth Widen, Caroline Hayward, Penelope A. Lind, Susan M. Ring, Lyle J. Palmer, Alexander Teumer, Kelly S. Benke, Christopher Oldmeadow, Katja Petrovic, Gonneke Willemsen, Andrew C. Heath, Harold Snieder, Jaakko Kaprio, Marja-Liisa Nuotio, Frank J. A. van Rooij, Robert M. Kirkpatrick, Nicholas G. Martin, Tomi E. Mäkinen, Michelle N. Meyer, Katri Räikkönen, Harm-Jan Westra, Daniel J. Benjamin, Jeffrey A. Boatman, Henrik Grönberg, Eva Albrecht, Sharon L.R. Kardia, Peter K. Joshi, Philip L. De Jager, Mariza de Andrade, Patricia A. Boyle, Jennifer R. Harris, Vilmundur Guonason, Christiaan de Leeuw, Juliette Harris, Dena G. Hernandez, Jingmei Li, Per Hall, Wei Zhao, Abdel Abdellaoui, Andres Metspalu, Christina Holzapfel, Stavroula Kanoni, Christopher F. Chabris, John Attia, Rauli Svento, Erasmus School of Economics, Epidemiology, Surgery, Neurology, Applied Economics, Research Methods and Techniques, Clinical Genetics, Internal Medicine, Child and Adolescent Psychiatry / Psychology, Econometrics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Biological Psychology, Functional Genomics, Management and Organisation, Tinbergen Institute, Amsterdam Neuroscience - Complex Trait Genetics, Rietveld, Cornelius A, Medland, Sarah E, Derringer, Jaime, Yang, Jian, Lee, Sang Hong, Koellinger, Philipp D, LifeLines Cohort Study, ABS Other Research (FEB), Reproductive Origins of Adult Health and Disease (ROAHD), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Public Health Research (PHR), Teaching and Teacher Education, Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes

Subjects
Netherlands Twin Register (NTR), Male, medicine.medical_specialty, Multifactorial Inheritance, Endophenotypes, social-science genetics, LOCI, SNP, Single-nucleotide polymorphism, Genome-wide association study, Biology, PREFERENCES, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Cognition, Polymorphism (computer science), medicine, GWAS, Humans, Allele, Polymorphism, education, gene, attainment, 030304 developmental biology, Genetics, 0303 health sciences, ENVIRONMENT, genome-wide association study, Multidisciplinary, Data Science, Replicate, Single Nucleotide, single-nucleotide polymorphism, linear polygenic score, ta3121, Educational attainment, Multidisciplinary Sciences, Educational Status, Female, Genetic Loci, Genome-Wide Association Study, educational attainment, Endophenotype, Medical genetics, 030217 neurology & neurosurgery
Abstract

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

Published
2013
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12. Linkage analysis for plasma amyloid beta levels in persons with hypertension implicates Abeta-40 levels to presenilin 2

Author

M. Arfan Ikram, Antonia M. W. Coppus, Maaike Schuur, John C. van Swieten, Irina V. Zorkoltseva, Ben A. Oostra, Yurii S. Aulchenko, Tatiana I. Axenovich, Cornelia M van Duijn, Najaf Amin, Marcel M. Verbeek, Monique M.B. Breteler, Carla A. Ibrahim-Verbaas, Aaron Isaacs, Neurology, Epidemiology, Radiology & Nuclear Medicine, Clinical Genetics, Human genetics, and NCA - Neurodegeneration

Subjects
Male, Presenilin-2/genetics, Genetic Linkage, Chromosomes, Human, Pair 11/genetics, Cohort Studies, PSEN2, Genetics (clinical), Netherlands, Genetics, education.field_of_study, biology, Amyloid beta-Peptides/blood, Single Nucleotide, Effective primary care and public health [NCEBP 7], Middle Aged, Hypertension/blood, Chromosomes, Human, Pair 1/genetics, Chromosomes, Human, Pair 1, Hypertension, Female, Human, Amyloid beta, DCN MP - Plasticity and memory, Population, Locus (genetics), Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Chromosomes, Pair 11/genetics, Alzheimer Disease, Genetic linkage, mental disorders, Presenilin-2, Pair 1/genetics, Humans, Genetic Predisposition to Disease, Polymorphism, education, Gene, DCN NN - Brain networks and neuronal communication, Aged, Genetic association, Alzheimer Disease/genetics, Amyloid beta-Peptides, Chromosomes, Human, Pair 11, Peptide Fragments, nervous system diseases, biology.protein, Lod Score, Peptide Fragments/blood
Abstract

Item does not contain fulltext Plasma concentrations of Abeta40 and Abeta42 rise with age and are increased in people with mutations that cause early-onset Alzheimer's disease (AD). Amyloid beta (Abeta) plasma levels were successfully used as an (endo)phenotype for gene discovery using a linkage approach in families with dominant forms of disease. Here, we searched for loci involved in Abeta plasma levels in a series of non-demented patients with hypertension in the Erasmus Rucphen Family study. Abeta40 and Abeta42 levels were determined in 125 subjects with severe hypertension. All patients were genotyped with a 6,000 single nucleotide polymorphisms (SNPs) illumina array designed for linkage analysis. We conducted linkage analysis of plasma Abeta levels. None of the linkage analyses yielded genome-wide significant logarithm of odds (LOD) score over 3.3, but there was suggestive evidence for linkage (LOD > 1.9) for two regions: 1q41 (LOD = 2.07) and 11q14.3 (LOD = 2.97), both for Abeta40. These regions were followed up with association analysis in the study subjects and in 320 subjects from a population-based cohort. For the Abeta40 region on chromosome 1, association of several SNPs was observed at the presenilin 2 gene (PSEN2) (p = 2.58 x 10(-4) for rs6703170). On chromosome 11q14-21, we found some association (p = 3.1 x 10(-3) for rs2514299). This linkage study of plasma concentrations of Abeta40 and Abeta42 yielded two suggestive regions, of which one points toward a known locus for familial AD.

Published
2012
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13. P1‐237: Genome‐Wide Association Study of Executive Function

Author

Stéphanie Debette, Cornelia M. van Duijn, Ian J. Deary, Gail Davies, Sudha Seshadri, J. C. Bis, Reinhold Schmidt, Albert V. Smith, Qiong Yang, Lina Zgaga, Jan Bressler, Mohammad Arfan Ikram, Monique M.B. Breteler, Caroline Hayward, Thomas H. Mosley, Carla A. Ibrahim-Verbaas, Lenore J. Launer, Helena Schmidt, Katja Petrovic, Maaike Schuur, Mirna Kirin, Annette L. Fitzpatrick, and James Wilson

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genome-wide association study, Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biology, Function (biology)
Published
2011
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14. O1‐01‐02: Genome‐wide association study of memory performance

Author

Gail Davies, Reinhold Schmidt, A. E. Smith, David A. Bennett, Katja Petrovic, Maaike Schuur, Monique M.B. Breteler, Carla A. Ibrahim-Verbaas, Stéphanie Debette, Sudha Seshadri, Mohammad Arfan Ikram, Cornelia M. van Duijn, Jim Stankovich, Helena Schmidt, Velandai Srikanth, Qiong Yang, Lina Zgaga, Harry Campbell, Caroline Hayward, Annette L. Fitzpatrick, Lei Yu, J. C. Bis, Thomas H. Mosley, Lenore J. Launer, Jan Bressler, Mirna Kirin, James Wilson, and Ian J. Deary

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genome-wide association study, Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biology, Memory performance
Published
2011
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15. Human Prion Diseases in The Netherlands (1998–2009): Clinical, Genetic and Molecular Aspects

Author

Patrizia Corrado, Gerard H. Jansen, Marcel M. Verbeek, Sabina Capellari, Piero Parchi, Annemieke J.M. Rozemuller, Matthew Bishop, Carla A. Ibrahim-Verbaas, Casper Jansen, Cornelia M. van Duijn, Willem A. van Gool, Rosaria Strammiello, Maaike Schuur, Wesley van Saane, Wim G. M. Spliet, Frank Baas, Erasmus MC other, Neurology, Epidemiology, Pathology, NCA - Neurodegeneration, Amsterdam Neuroscience, Genome Analysis, Jansen C., Parchi P., Capellari S., Ibrahim-Verbaas C.A., Schuur M., Strammiello R., Corrado P., Bishop M.T., van Gool W.A., Verbeek M.M., Baas F., van Saane W., Spliet W.G., Jansen G.H., van Duijn C.M., and Rozemuller A.J.

Subjects
Male, Pathology, Epidemiology, lcsh:Medicine, Disease, Creutzfeldt-Jakob Syndrome, Prion Diseases, PRION TYPING, Genotype, PRION DISEASE, lcsh:Science, Netherlands, Aged, 80 and over, Multidisciplinary, Mortality rate, Incidence (epidemiology), Neurodegenerative Diseases, Middle Aged, Neurology, Medicine, Infectious diseases, Female, PRNP, Alzheimer's disease, Research Article, Adult, Prion diseases, medicine.medical_specialty, Prions, DCN MP - Plasticity and memory, CLASSIFICATION, SDG 3 - Good Health and Well-being, Genetics, medicine, Humans, Dementia, Biology, DCN NN - Brain networks and neuronal communication, Aged, Population Biology, Gerstmann-Straussler-Scheinker disease, business.industry, lcsh:R, medicine.disease, Creutzfeldt-Jakob disease, nervous system diseases, Fatal familial insomnia, lcsh:Q, business, Population Genetics
Abstract

Contains fulltext : 108169.pdf (Publisher’s version ) (Open Access) Prion diseases are rare and fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. Based on a national surveillance program in the Netherlands we describe here the clinical, neuropathological, genetic and molecular characteristics of 162 patients with neuropathologically confirmed prion disease over a 12-year period (1998-2009). Since 1998, there has been a relatively stable mortality of Creutzfeldt-Jakob disease (CJD) in the Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in all patients with sporadic CJD (sCJD) showed a trend for under-representation of VV cases (7.0%), compared with sCJD cohorts in other Western countries, whereas the MV genotype was relatively over-represented (22,4%). Combined PrP(Sc) and histopathological typing identified all sCJD subtypes known to date, except for the VV1 subtype. In particular, a "pure" phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one FFI and four GSS cases. Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with new variant CJD (1.9%) and one with variably protease-sensitive prionopathy (VPSPr). Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer's disease (21.2%) or vascular causes of dementia (19.9%). The mortality rates of sCJD in the Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the VV2 sCJD subtype compared to that reported to date in other Western countries deserves further investigation.

Published
2012
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