Genetic study of multimodal imaging Alzheimer’s disease progression score implicates novel loci
Year: 2018
Type: article
Study design: Observational Study
Abstract: Identifying genetic risk factors underpinning different aspects of Alzheimer's disease has the potential to provide important insights into pathogenesis. Moving away from simple case-control definitions, there is considerable interest in using quantitative endophenotypes, such as those derived from imaging as outcome measures. Previous genome-wide association studies of imaging-derived biomarkers in sporadic late-onset Alzheimer's disease focused only on phenotypes derived from single imaging modalities. In contrast, we computed a novel multi-modal neuroimaging phenotype comprising cortical amyloid burden and bilateral hippocampal volume. Both imaging biomarkers were used as input to a disease progression modelling algorithm, which estimates the biomarkers' long-term evolution curves from population-based longitudinal data. Among other parameters, the algorithm computes the shift in time required to optimally align a subjects' biomarker trajectories with these population curves. This time shift serves as a disease progression score and it was used as a quantitative trait in a discovery genome-wide association study with n = 944 subjects from the Alzheimer's Disease Neuroimaging Initiative database diagnosed as Alzheimer's disease, mild cognitive impairment or healthy at the time of imaging. We identified a genome-wide significant locus implicating LCORL (rs6850306, chromosome 4; P = 1.03 × 10-8). The top variant rs6850306 was found to act as an expression quantitative trait locus for LCORL in brain tissue. The clinical role of rs6850306 in conversion from healthy ageing to mild cognitive impairment or Alzheimer's disease was further validated in an independent cohort comprising healthy, older subjects from the National Alzheimer's Coordinating Center database. Specifically, possession of a minor allele at rs6850306 was protective against conversion from mild cognitive impairment to Alzheimer's disease in the National Alzheimer's Coordinating Center cohort (hazard ratio = 0.593, 95% confidence interval = 0.387-0.907, n = 911, PBonf = 0.032), in keeping with the negative direction of effect reported in the genome-wide association study (βdisease progression score = -0.07 ± 0.01). The implicated locus is linked to genes with known connections to Alzheimer's disease pathophysiology and other neurodegenerative diseases. Using multimodal imaging phenotypes in association studies may assist in unveiling the genetic drivers of the onset and progression of complex diseases.
Source: Brain
DOI: 10.1093/brain/awy141
Institutions: University College London, Stanford Medicine, Stanford University, Institut national de recherche en sciences et technologies du numérique, Université Côte d'Azur, EPIONE: E-Patient : Images, données & mOdèles pour la médeciNe numériquE, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,222
Funders: Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Biogen, University of Southern California, F. Hoffmann-La Roche, Meso Scale Diagnostics, BioClinica, Novartis Pharmaceuticals Corporation, Northern California Institute for Research and Education, Wellcome Trust, Brain Research UK, Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease, National Alzheimer's Coordinating Center, National Institute for Health and Care Research, Brain Research Trust, University College London, European Commission, Institut National de la Santé et de la Recherche Médicale, Bundesministerium für Bildung und Forschung, Erasmus Medisch Centrum, Eisai, University College London Hospitals NHS Foundation Trust, Servier, Hjartavernd, H. Lundbeck A/S, Centre hospitalier régional universitaire de Lille, IXICO, National Institutes of Health, Genentech, Canadian Institutes of Health Research, Medical Research Council, Engineering and Physical Sciences Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Neurological Disorders and Stroke, FP7 Information and Communication Technologies, Common Fund
Awards: G1068845026, G1106781614, G1108310052, G1161633587, G1218215880, G1234573687, G1263262031, Kompetenznetz 'Demenzen', Michigan Alzheimer's Disease Core Center, UC Davis Alzheimer's Disease Core Center, Indiana Alzheimer Disease Center, G1366216728, G150562299, EPSRC Centre for Doctoral Training in Medical Imaging, G1694405320, G1737639950, G1775974636, Wake Forest Alzheimer's Disease Core Center, G1901425420, G2013140284, G230712557, G2398422634, University of Kentucky Alzheimer's Disease Core Center, VPH Dementia Research Enabled by IT, Neurobiology of Alzheimer's Disease and Aging, G2697093250, G282710236, G2929235049, G3026342146, G3057370048, Alzheimer's Disease Research Center, G3126617770, G3161882281, G3218891203, National Alzheimer's Coordinating Center, UCSD Alzheimer's Disease Research Center P50, G3386955339, G346328595, Alzheimer's Disease Research Center, G3734040457, G3876327265, G3916087950, Intelligent Imaging: Motion, Form and Function Across Scale, G4082276054, G4122031276, Computational models of neurodegenerative disease progression, G422312149, Data-driven models for Progression Of Neurological Disease, Alzheimer's Disease Core Center, The Alzheimer's Disease Research Center at the University of California, Irvine, G4358921014, G4421367155, Stanford Alzheimer's Disease Research Center, G4591121360, G469773307, G4811888002, G4838234079, G4874008555, Oregon Alzheimer's Disease Center, G5017848241, Rush Alzheimer's Disease Core Center, G503540700, G5123081433, Alzheimer's Disease Genetics Consortium, G5314163940, G5334218988, G5598714753, G5780694236, G5814724622, CHARGE consortium: omics discovery for CVD and aging phenotypes, Alzheimer's Disease Core Center, Alzheimer's Disease Research Center - Overall, G6256152478, G6258606120, A Powerful, Genome-Wide Association Scan for Susceptibility Genes for late-onset Alzheimer's disease, Verbundprojekt: Kompetenznetz Demenzen - Epidemiologie: Teilprojekte der Universität Bonn, G639185302, G6425121803, G6445626367, Wisconsin Alzheimer's Disease Research Center, G6478811163, G6496510108, University of Kansas Alzheimer's Disease Core Centers, G6708752960, G6801832960, Alzheimer's Disease Research Center, G696815201, Alzheimer Disease Research Center, Yale Alzheimer Disease Research Center, G7042289108, Arizona Alzheimer's Disease Core Center, Verbundprojekt Kompetenznetz Demenzen: Teilprojekte des ZISG Mannheim (2. Förderphase), Johns Hopkins Alzheimer's Disease Research Center, G7148903907, G7176475171, MICA: Medical Bioinformatics: Data-Driven Discovery for Personalised Medicine, G7243260849, G7252003062, G7373387228, G745803450, G748345579, G7576515556, Boston University Alzheimer's Disease Center, Alzheimer's Disease Research Center, Massachusetts Alzheimer's Disease Research Center, Alzheimer's Disease Core Center, Emory Alzheimer's Disease Center, University of Florida - Mt. Sinai Medical Center AD Research Center, AD Gene Discovery: Exome Chip, New Endophenotypes & Functional Studies in CHARGE, G8486820766, G8488061998, G8620018032, G863491659, G8650869886, EPICure@19 - the extremely preterm young adult, G8936014493, G8951052545, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), New Approaches to Dementia Heterogeneity, Mayo Alzheimer's Disease Research Center, G991187644
OpenAlex ID: W2802278070