The causes and consequences of Alzheimer’s disease: phenome-wide evidence from Mendelian randomization
Year: 2022
Type: article
Study design: Observational Study
Abstract: ABSTRACT Importance Alzheimer’s disease is the leading cause of disability and healthy life years lost. However, to date, there are no proven causal and modifiable risk factors, or effective interventions. Objective We aimed to identify: a) factors modified by prodromal Alzheimer’s disease pathophysiology and b) causal risk factors for Alzheimer’s disease. We identified factors modified by Alzheimer’s disease using a phenome-wide association study (PheWAS) on the Alzheimer’s disease polygenic risk score (PRS) (p≤5×10 -8 ), stratified by age tertiles. We used two-sample bidirectional Mendelian randomization (MR) to estimate the causal effects of identified risk factors and correlates on liability for Alzheimer’s disease. Design, setting, and participants 334,968 participants of the UK Biobank aged 39 to 72 years old (111,656 in each tertile) met our eligibility criteria. Exposures Standardized weighted PRS for Alzheimer’s disease at p≤5×10 -8 . Main outcomes and measures All available phenotypes in UK Biobank, including data on health and lifestyle, as well as samples from urine, blood and saliva, at the time of analysis. Results Genetic liability for Alzheimer’s disease was associated with red blood cell indices and cognitive measures at all ages. In the middle and older age tertiles, ages 53 and above, higher genetic liability for Alzheimer’s disease was adversely associated with medical history (e.g. atherosclerosis, use of cholesterol-lowering medications), physical measures (e.g. body fat measures), blood cell indices (e.g. red blood cell distribution width), cognition (e.g. fluid intelligence score) and lifestyle (e.g. self-reported moderate activity). In follow-up analyses using MR, there was only evidence that education, fluid intelligence score, hip circumference, forced vital capacity, and self-reported moderate physical activity were likely to be causal risk factors for Alzheimer’s disease. Conclusion and relevance Genetic liability for Alzheimer’s disease is associated with over 160 phenotypes, some as early as age 39 years. However, findings from MR analyses imply that most of these associations are likely to be a consequence of prodromal disease or selection, rather than a cause of the disease.
Source: Nature Communications
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,890
Funders: Vanderbilt University, University of Miami, University of Pennsylvania, Stiftelsen Kristian Gerhard Jebsen, Case Western Reserve University, Norges Teknisk-Naturvitenskapelige Universitet, Wellcome Trust, Broad Institute, Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease, National Alzheimer's Coordinating Center, University of Bristol, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, University of Toronto, Helse Midt-Norge, Norges Forskningsråd, St. Olavs Hospital Universitetssykehuset i Trondheim, National Institutes of Health, Fakultet for medisin og helsevitenskap, Norges Teknisk-Naturvitenskapelige Universitet, Medical Research Council, Economic and Social Research Council, Faculty of Medicine and Health, University of Sydney, Norwegian Institute of Public Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, U.S. National Library of Medicine
Awards: G1052397333, G1135917780, G1182606701, G1218215880, G1243299691, G1460387277, G149876332, G1527150935, THE AGES STUDY - THE REYKJAVIK STUDY OF HEALTHY AGING FOR THE NEW MILLENUM, G1643655829, G1691174148, G173303992, G1941623656, CHARGE: Identifying Risk & Protective SNV for AD in ADSP Case-control Sample, Large Scale Sequencing and Analysis of Genomes, G2193588257, G230712557, G235045266, G2452660645, G2538597952, G2564988809, G2673957436, G2818629771, A Platform for Large-Scale Genomic Discovery, G2957837340, G301743239, G3114902838, G3233549029, National Alzheimer's Coordinating Center, Développement de stratégies innovantes pour une approche transdisciplinaire de la maladie d'Alzheime, G3368247964, G3410686264, G3462919067, G384457986, G3916087950, G4167445418, G4200864717, Informing educational interventions using genome-wide data: causal evidence from 573,586 participants of eight cohort studies, Analysing the emergence of anti-microbial resistance among different bacterial species, The Human Genome Sequencing Center, G457330776, G482473366, G4998334444, G5001017760, G5074086979, Alzheimer's Disease Genetics Consortium, G5470336846, Life course aetiology of dementia and cognitive decline: improving causal inference, G5558075022, G567847597, G571894948, G5850737185, CHARGE consortium: omics discovery for CVD and aging phenotypes, G6033034647, Consortium for Alzheimers Sequence Analysis (CASA), Sequence-based Discovery of AD Risk & Protective Alleles, G6195637971, A Powerful, Genome-Wide Association Scan for Susceptibility Genes for late-onset Alzheimer's disease, G6548750934, G6648385527, Mendelian randomization to hypothesis-free causal inference, G7046104286, G7051404557, G7406331046, G7431531211, G7448564355, G770899802, Mediation analysis in life course epidemiology: methodological innovation and application to studies of obesity and cardiometabolic health, Sequence-based Discovery of AD Risk & Protective Alleles, G7955974312, G7990456425, Modifier Genes that Influence Age at Onset or Protect Against Development of Alzheimer's Disease (AD), AD Gene Discovery: Exome Chip, New Endophenotypes & Functional Studies in CHARGE, G8502142660, G8518790725, G8575094079, Building on GWAS for NHLBI-disease: the CHARGE consortium, Genome Center for Alzheimer's Disease (GCAD), THE NIA GENETICS OF ALZHEIMER'S DISEASE DATA STORAGE SITE, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)
OpenAlex ID: W4290803778