title: Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease.
abstract: The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4<p-value<0.05), were found to be rare coding variants (0.009%<MAF<1.4%) with moderate to strong effect size (1.84<OR<Inf) that map to genes mainly involved in Aβ extracellular degradation (TTR, ACE), clearance (LRP1) and APP trafficking and recycling (SORL1). These results were partially replicated in the gene-based analysis (c-alpha and SKAT tests), that reports ECE1, LYZ and TTR as nominally associated to AD (1.7e-3 <p-value <0.05). In concert with previous studies, we suggest that 1) common coding variability in APP-Aβ genes is not a critical factor for AD development and 2) Aβ degradation and clearance, rather than Aβ production, may play a key role in the etiology of sporadic AD.
authors.affiliation: Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.|Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States of America.|Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charite' Universitätmedizin, Berlin, Germany.|German Center for Neurodegenerative Diseases (DZNE), Berlin site, Germany.
authors.forename: Celeste
authors.initials: C
authors.lastname: Sassi
authors.affiliation: Departments of Biology, Neuroscience, Brigham Young University, Provo, UT, United States of America.
authors.forename: Perry G
authors.initials: PG
authors.lastname: Ridge
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Raphael
authors.initials: R
authors.lastname: Gibbs
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.affiliation: King's College London Institute of Psychiatry, London, United Kingdom.|QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Lupton
authors.affiliation: King's College London Institute of Psychiatry, London, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: King's College London Institute of Psychiatry, London, United Kingdom.
authors.forename: Katie
authors.initials: K
authors.lastname: Lunnon
authors.affiliation: King's College London Institute of Psychiatry, London, United Kingdom.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.affiliation: Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Kristelle S
authors.initials: KS
authors.lastname: Brown
authors.affiliation: Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Medway
authors.affiliation: Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lord
authors.affiliation: Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Turton
authors.affiliation: Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.affiliation: King's College London Institute of Psychiatry, London, United Kingdom.
authors.forename: John F
authors.initials: JF
authors.lastname: Powell
authors.affiliation: Departments of Biology, Neuroscience, Brigham Young University, Provo, UT, United States of America.
authors.forename: John S
authors.initials: JS
authors.lastname: Kauwe
authors.affiliation: Washington University, Division of Biology and Biomedical Sciences St. Louis, MO, United States of America.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
authors.affiliation: Icahn School of Medicine at Mount Sinai, Icahn Medical Institute, New York, NY, United States of America.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.affiliation: Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D059472:Exome; D006801:Humans
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor