Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
25104557
TITLE
Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease.
ABSTRACT
The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias.
Copyright © 2014 Elsevier Inc. All rights reserved.
DATE PUBLISHED
2014 Dec
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2014/04/20
revised 2014/06/06
accepted 2014/06/07
aheadofprint 2014/06/16
entrez 2014/08/09 06:00
pubmed 2014/08/12 06:00
medline 2015/11/10 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Sassi C Sassi Celeste C Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Electronic address: celeste.sassi.10@ucl.ac.uk.
Guerreiro R Guerreiro Rita R Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Gibbs R Gibbs Raphael R Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Ding J Ding Jinhui J Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Lupton MK Lupton Michelle K MK King's College London Institute of Psychiatry, London, UK.
Troakes C Troakes Claire C King's College London Institute of Psychiatry, London, UK.
Al-Sarraj S Al-Sarraj Safa S King's College London Institute of Psychiatry, London, UK.
Niblock M Niblock Michael M King's College London Institute of Psychiatry, London, UK.
Gallo JM Gallo Jean-Marc JM King's College London Institute of Psychiatry, London, UK.
Adnan J Adnan Jihad J King's College London Institute of Psychiatry, London, UK.
Killick R Killick Richard R King's College London Institute of Psychiatry, London, UK.
Brown KS Brown Kristelle S KS Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
Medway C Medway Christopher C Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
Lord J Lord Jenny J Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
Turton J Turton James J Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
Bras J Bras Jose J Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
Alzheimer's Research UK Consortium
Morgan K Morgan Kevin K Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
Powell JF Powell John F JF King's College London Institute of Psychiatry, London, UK.
Singleton A Singleton Andrew A Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Hardy J Hardy John J Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
INVESTIGATORS
JOURNAL
VOLUME: 35
ISSUE: 12
TITLE: Neurobiology of aging
ISOABBREVIATION: Neurobiol. Aging
YEAR: 2014
MONTH: Dec
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1558-1497
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Neurobiol Aging
COUNTRY: United States
ISSNLINKING: 0197-4580
NLMUNIQUEID: 8100437
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
089698 Wellcome Trust United Kingdom
089701 Wellcome Trust United Kingdom
G1100695 Medical Research Council United Kingdom
WT089698 Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
KEYWORD
APP
Alzheimer's disease
Exome sequencing
GRN
MAPT
Neurodegenerative dementia
PRNP
PSEN1
PSEN2
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Aged
Aged, 80 and over
Alzheimer Disease genetics
Amyloid beta-Protein Precursor genetics
Cohort Studies genetics
Dementia genetics
Diagnosis, Differential genetics
Female genetics
Genetic Association Studies genetics
Genetic Predisposition to Disease genetics
Genetic Testing genetics
Genetic Variation genetics
Humans genetics
Intercellular Signaling Peptides and Proteins genetics
Male genetics
Middle Aged genetics
Presenilin-1 genetics
Presenilin-2 genetics
Prions genetics
tau Proteins genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 APP protein, human
0 Amyloid beta-Protein Precursor
0 GRN protein, human
0 Intercellular Signaling Peptides and Proteins
0 MAPT protein, human
0 PRNP protein, human
0 PSEN1 protein, human
0 PSEN2 protein, human
0 Presenilin-1
0 Presenilin-2
0 Prions
0 tau Proteins
OTHER ID's
OTHERID SOURCE
PMC4236585 NLM