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1. Largest GWAS (N=1,126,563) of Alzheimer’s Disease Implicates Microglia and Immune Cells

Author

Tore Wergeland Meisingset, Kari Stefansson, Shahram Bahrami, Sigurdur H. Magnusson, Tormod Fladby, Ingunn Bosnes, Lavinia Athanasiu, Danielle Posthuma, Sigrid Botne Sando, Stephan Ripke, Linda M. Pedersen, Amy E Martinsen, Dag Aarsland, Ole Kristian Drange, Henrik Zetterberg, Alexey A. Shadrin, Margda Waern, Steinunn Thordardottir, Sigrid Børte, Wei Zhou, Kristian Hveem, Marianne Bakke Johnsen, Julia M. Sealock, Eystein Stordal, Geir Selbæk, Silke Kern, John-Anker Zwart, Iris E. Jansen, Palmi V. Jonsson, Ole A. Andreassen, Ingvild Saltvedt, Ingmar Skoog, Maiken Elvestad Gabrielsen, Cristen J. Willer, Chandra A. Reynolds, Ingun Ulstein, Arvid Rongve, Anne Heidi Skogholt, Douglas P Wightman, Richard Dobson, Anna Zettergren, Lea K. Davis, Nancy L. Pedersen, Ida K. Karlsson, Srdjan Djurovic, Kaj Blennow, Laurent F. Thomas, Latha Velayudhan, Angela Hodges, Bendik S. Winsvold, Jon Snaedal, Lars G. Fritsche, Hreinn Stefansson, Petra Proitsi, Jeanne E. Savage, Jonas B. Nielsen, and Geir Bråthen

Subjects
Genetics, medicine.anatomical_structure, Immune system, Drug development, Amyloid, Microglia, medicine, Dementia, Genome-wide association study, Disease, Biology, medicine.disease, Gene
Abstract

SummaryLate-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases1. Late-onset Alzheimer’s disease is caused by a combination of many genetic variants with small effect sizes and environmental influences. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified2,3. Here we show that increased sample sizes allowed for identification of seven novel genetic loci contributing to Alzheimer’s disease. We highlighted eight potentially causal genes where gene expression changes are likely to explain the association. Human microglia were found as the only cell type where the gene expression pattern was significantly associated with the Alzheimer’s disease association signal. Gene set analysis identified four independent pathways for associated variants to influence disease pathology. Our results support the importance of microglia, amyloid and tau aggregation, and immune response in Alzheimer’s disease. We anticipate that through collaboration the results from this study can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants which contribute to Alzheimer’s pathology. Furthermore, the increased understanding of the mechanisms that mediate the effect of genetic variants on disease progression will help identify potential pathways and gene-sets as targets for drug development.

Published
2020
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2. 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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3. A functional polymorphism of the brain derived neurotrophic factor gene and cortical anatomy in autism spectrum disorder

Author

Armin Raznahan, Declan G. Murphy, Tomáš Paus, Patrick Bolton, Petra Proitsi, Roberto Toro, and John Powell

Subjects
Brain-derived neurotrophic factor, Autism, Cognitive Neuroscience, Neuropsychology, Brain, Anatomy, medicine.disease, Article, Pathology and Forensic Medicine, Neuroimaging, Autism spectrum disorder, Posterior cingulate, Pediatrics, Perinatology and Child Health, Neuroplasticity, medicine, Neurology (clinical), Brain derived neurotrophic factor, Psychology, Gyrification, Neuroscience, MRI
Abstract

Autism Spectrum Disorder (ASD) is associated with both (i) post-mortem and neuroimaging evidence of abnormal cortical development, and (ii) altered signalling in Brain Derived Neurotrophic Factor (BDNF) pathways - which regulate neuroproliferative and neuroplastic processes. In healthy controls genotype at a single nucleotide polymorphism that alters BDNF signalling (Val66met) has been related to regional cortical volume. It is not known however if this influence on brain development is intact in ASD. Therefore we compared the relationship between genotype and cortical anatomy (as measured using in vivo Magnetic Resonance Imaging) in 41 people with ASD and 30 healthy controls. We measured cortical volume, and its two sole determinants - cortical thickness and surface area - which reflect differing neurodevelopmental processes. We found “Group-by-Genotype” interactions for cortical volume in medial (caudal anterior cingulate, posterior cingulate) and lateral (rostral middle, lateral orbitofrontal, pars orbitalis and pars triangularis) frontal cortices. Furthermore, within (only) these regions “Group-by-Genotype” interactions were also found for surface area. No effects were found for cortical thickness in any region. Our preliminary findings suggest that people with ASD have differences from controls in the relationship between BDNF val66met genotype and regional (especially frontal) cortical volume and surface area, but not cortical thickness. Therefore alterations in the relationship between BDNF val66met genotype and surface area in ASD may drive the findings for volume. If correct, this suggests ASD is associated with a distorted relationship between BDNF val66met genotype and the determinants of regional cortical surface area – gyrification and/or sulcal positioning.

Published
2009
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4. Complement Factor H Y402H Polymorphism is not Associated with Late-onset Alzheimer’s Disease

Author

Michael Conlon O'Donovan, Gillian Hamilton, John Powell, Petra Proitsi, Julie Williams, Simon Lovestone, and Michael John Owen

Subjects
medicine.medical_specialty, Neurology, Genotype, Late onset, Disease, Biology, Polymorphism, Single Nucleotide, Cohort Studies, Pathogenesis, Cellular and Molecular Neuroscience, Gene Frequency, Alzheimer Disease, medicine, Humans, SNP, Genetic Predisposition to Disease, Age of Onset, Gene, Aged, DNA, Amino Acid Substitution, Complement Factor H, Factor H, Immunology, Alternative complement pathway, Molecular Medicine
Abstract

There is evidence to suggest a role for immune dysfunction in the pathogenesis of Alzheimer's disease, and it has previously been shown that blood plasma levels of the protein complement factor H, a member of the alternative complement pathway, was specifically elevated in people with late-onset Alzheimer's disease. We have genotyped the common complement factor H Y402H polymorphism in a large case-control cohort to investigate association with late-onset Alzheimer's disease susceptibility and find no evidence that this SNP is associated with disease risk. However, it remains possible that another variant in this gene may modify susceptibility for late-onset Alzheimer's disease.

Published
2007
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5. Candidate gene association study of insulin signaling genes and Alzheimer's disease: evidence for SOS2, PCK1, and PPARgamma as susceptibility loci

Author

Petra Proitsi, John Powell, Angharad R. Morgan, Julie Williams, Simon Lovestone, Michael Conlon O'Donovan, Michael John Owen, Luke Jehu, and Gillian Hamilton

Subjects
Male, Candidate gene, Potassium Channels, Receptors, Drug, Single-nucleotide polymorphism, Locus (genetics), Disease, Biology, Sulfonylurea Receptors, Polymorphism, Single Nucleotide, Genetic determinism, Cellular and Molecular Neuroscience, Gene Frequency, Alzheimer Disease, Genetic model, medicine, Humans, Insulin, Genetic Predisposition to Disease, Age of Onset, Potassium Channels, Inwardly Rectifying, Genetics (clinical), Aged, Genetics, Aged, 80 and over, Sex Characteristics, Haplotype, Intracellular Signaling Peptides and Proteins, medicine.disease, United Kingdom, PPAR gamma, Psychiatry and Mental health, Haplotypes, Son of Sevenless Proteins, ATP-Binding Cassette Transporters, Female, Phosphoenolpyruvate Carboxykinase (GTP), Alzheimer's disease, Signal Transduction
Abstract

Epidemiological evidence supports the existence of a possible link between type II diabetes mellitus (T2DM) and late-onset Alzheimer's disease (LOAD). Polymorphisms from candidate genes for T2DM were genotyped in a two-stage approach to identify novel risk factors for LOAD. One hundred fifty-two polymorphisms were initially genotyped in a case:control cohort: nine SNPs showed individual association with disease status under at least one genetic model, while an additional two SNPs showed a haplotype association. In a replication study, we confirmed significant association of SNPs within three genes--PPARgamma, SOS2, and PCK1--with Alzheimer's disease. In particular, our data suggest that the effect of variants within these genes might be influenced by gender.

Published
2007

6. P1–326: Statistical and genetic studies on the psychosis sub–phenotype in Alzheimer's disease

Author

Gillian Hamilton, C. Foy, John Powell, Julie Williams, Paul Hollinworth, Petra Proitsi, Michael John Owen, Simon Lovestone, and Nicola Archer

Subjects
Psychosis, Epidemiology, business.industry, Health Policy, Disease, medicine.disease, Phenotype, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Immunology, medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2006
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7. Erratum: Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

Author

Michael Conlon O'Donovan, Markus M. Nöthen, D P De Deyn, Heinz Erich Wichmann, Michelle K. Lupton, Andrew McQuillin, Gill Livingston, Michael Hüll, Kauwe Jsk., Nick C. Fox, Carlos Cruchaga, Bernadette McGuinness, Norman Klopp, Sebastiaan Engelborghs, A. D. Smith, Jens Wiltfang, Panagiotis Deloukas, Richard Abraham, Karolien Bettens, Denise Harold, Martin Dichgans, Britta Schürmann, Valentina Moskvina, Frank Jessen, Amy Williams, Julie Williams, Lutz Frölich, Alison Goate, Kevin Morgan, Johannes Kornhuber, Carol Brayne, Susanne Moebus, John Hardy, J Singh Pahwa, John Collinge, M. J. Owen, Alexandra Stretton, Ammar Al-Chalabi, Aoibhinn Lynch, Seth Love, Nicola Jones, C. Van Broeckhoven, Rita Guerreiro, Kevin Mayo, Martin N. Rossor, Stephen Todd, Minerva M. Carrasquillo, Kristelle Brown, Wolfgang Maier, Karl-Heinz Jöckel, Michael Gill, Rebecca Sims, John C. Morris, Petra Nowotny, Angharad R. Morgan, Hugh Gurling, Dan Rujescu, Simon Lovestone, Peter Passmore, Peter Holmans, Harald Hampel, Steve Younkin, Simon Mead, H Van Den Bussche, Rhian Gwilliam, Petra Proitsi, AB Singleton, Kimberley Dowzell, Marian L. Hamshere, Charlene Thomas, V. Pankratz, Magda Tsolaki, David Craig, Christopher Shaw, Kristel Sleegers, Christopher Holmes, Brian A. Lawlor, N Bass, Isabella Heuser, John Powell, Patrick G. Kehoe, Amy Gerrish, D. M. A. Mann, David C. Rubinsztein, T W Mühleisen, and Paul Hollingworth

Subjects
Genetics, Genome-wide association study, Disease, Biology, PICALM
Published
2009
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8. P1-014 Principal components analysis of the neuropsychiatric inventory in Alzheimer's disease

Author

Carol Brayne, Brain Lawlor, John Powell, David C. Rubinsztein, Michael John Owen, Marian L. Hamshere, Ivor Evans, Julie Williams, Amanda J. Edmondson, Aoibhinn Lynch, Rebecca M. Ludford, Paul Hollingworth, Michael Gill, Catherine Foy, Petra Proitsi, Pam Moore, Simon Lovestone, G Hill, Nicola Archer, and Barbara-Anna Hamilton

Subjects
Aging, General Neuroscience, Principal component analysis, Neurology (clinical), Disease, Geriatrics and Gerontology, Neuropsychiatric inventory, Psychology, Developmental Biology, Clinical psychology
Published
2004
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