Initial Assessment of the Pathogenic Mechanisms of the recently identified Alzheimer Risk Loci

Patrick Holton; Mina Ryten; Michael Nalls; Daniah Trabzuni; Michael E Weale; Dena Hernandez; Helen Crehan; J. Raphael Gibbs; Richard Mayeux; Jonathan L Haines; Lindsay A Farrer; Margaret A Pericak-Vance; Gerard D Schellenberg; Manuel Ramirez-Restrepo; Anzhelika Engel; Amanda J Myers; Jason J Corneveaux; Matthew J Huentelman; Allissa Dillman; Mark R Cookson; Eric M Reiman; Andrew Singleton; John Hardy; Rita Guerreiro

doi:10.1111/ahg.12000

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Initial Assessment of the Pathogenic Mechanisms of the recently identified Alzheimer Risk Loci

Journal article

Open access

Peer reviewed

Initial Assessment of the Pathogenic Mechanisms of the recently identified Alzheimer Risk Loci

Patrick Holton, Mina Ryten, Michael Nalls, Daniah Trabzuni, Michael E Weale, Dena Hernandez, Helen Crehan, J. Raphael Gibbs, Richard Mayeux, Jonathan L Haines, …

Annals of human genetics, Vol.77(2), pp.85-105

2013-03

DOI: https://doi.org/10.1111/ahg.12000

PMCID: PMC3578142

PMID: 23360175

Abstract

Alzheimer’s disease

GWAS

genetic risk

Recent genome wide association studies have identified CLU , CR1 , ABCA7 BIN1 , PICALM and MS4A6A / MS4A6E in addition to the long established APOE , as loci for Alzheimer’s disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology. Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer’s disease.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.57 Alzheimer's Disease
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Initial Assessment of the Pathogenic Mechanisms of the recently identified Alzheimer Risk Loci
Creators: Patrick Holton - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Mina Ryten - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Michael Nalls - Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Daniah Trabzuni - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Michael E Weale - Department of Medical & Molecular Genetics, King’s College London, Guy’s Hospital, London, UK
Dena Hernandez - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Helen Crehan - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
J. Raphael Gibbs - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Richard Mayeux - Gertrude H. Sergievsky Center and Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY
Jonathan L Haines - Department of Molecular Physiology and Biophysics and Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN
Lindsay A Farrer - Departments of Medicine (Biomedical Genetics), Biostatistics, Ophthalmology, Epidemiology, and Neurology, Boston University Schools of Medicine and Public Health, Boston, MA
Margaret A Pericak-Vance - The John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL
Gerard D Schellenberg - Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
Manuel Ramirez-Restrepo - Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL
Anzhelika Engel - Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL
Amanda J Myers - Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL
Jason J Corneveaux - Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, Phoenix, AZ
Matthew J Huentelman - Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, Phoenix, AZ
Allissa Dillman - Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Mark R Cookson - Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Eric M Reiman - Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, Phoenix, AZ
Andrew Singleton - Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
John Hardy - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Rita Guerreiro - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Publication Details: Annals of human genetics, Vol.77(2), pp.85-105
Academic Unit: Miller School of Medicine; Cell Biology Research; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 23360175
PMCID: PMC3578142
Record Identifier: 991031559511202976