Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study

Soren D. Ostergaard; Shubhabrata Mukherjee; Stephen J. Sharp; Petroula Proitsi; Luca A. Lotta; Felix Day; John R. B. Perry; Kevin L. Boehme; Stefan Walter; John S. Kauwe; Laura E. Gibbons; Eric B. Larson; John F. Powell; Claudia Langenberg; Paul K. Crane; Nicholas J. Wareham; Robert A. Scott; Alzheimer's Dis Genetics; Panos Deloukas

doi:10.1371/journal.pmed.1001841

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Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study

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Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study

Soren D. Ostergaard, Shubhabrata Mukherjee, Stephen J. Sharp, Petroula Proitsi, Luca A. Lotta, Felix Day, John R. B. Perry, Kevin L. Boehme, Stefan Walter, John S. Kauwe, …

PLoS medicine, Vol.12(6), pp.e1001841; discussion e1001841-e1001841; discussion e1001841

01/06/2015

DOI: https://doi.org/10.1371/journal.pmed.1001841

PMCID: PMC4469461

PMID: 26079503

Abstract

General & Internal Medicine

Life Sciences & Biomedicine

Medicine, General & Internal

Science & Technology

Background Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). Methods and Findings We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, N-SNPs = 49), fasting glucose (N-SNPs = 36), insulin resistance (N-SNPs = 10), body mass index (BMI, N-SNPs = 32), total cholesterol (N-SNPs = 73), HDL-cholesterol (N-SNPs = 71), LDL-cholesterol (N-SNPs = 57), triglycerides (N-SNPs = 39), systolic blood pressure (SBP, N-SNPs = 24), smoking initiation (N-SNPs = 1), smoking quantity (N-SNPs = 3), university completion (N-SNPs = 2), and years of education (N-SNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 x 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 x 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 x 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. Conclusions Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure-or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications-may reduce AD risk.

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Title: Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study
Creators - without role: Soren D. Ostergaard - Aarhus University
Shubhabrata Mukherjee - University of Washington
Stephen J. Sharp - MRC Epidemiology Unit
Petroula Proitsi - King's College London
Luca A. Lotta - MRC Epidemiology Unit
Felix Day - MRC Epidemiology Unit
John R. B. Perry - MRC Epidemiology Unit
Kevin L. Boehme - Brigham Young University
Stefan Walter - University of California, San Francisco
John S. Kauwe - Brigham Young University
Laura E. Gibbons - University of Washington
Eric B. Larson - University of Washington
John F. Powell - King's College London
Claudia Langenberg - University of Cambridge
Paul K. Crane - University of Washington
Nicholas J. Wareham - University of Cambridge
Robert A. Scott - MRC Epidemiology Unit
Alzheimer's Dis Genetics
Panos Deloukas - King Abdulaziz University
Publication Details: PLoS medicine, Vol.12(6), pp.e1001841; discussion e1001841-e1001841; discussion e1001841
Publisher: Public Library Science
Number of pages: 16
Grant note: Heinz Nixdorf Foundation R01 NS059873 / National Institutes of Health, National Institute on Aging (NIH-NIA), TGen Northern California Institute for Research and Education from Elan Corporation Glaxo Smith Kline; GlaxoSmithKline AG025688 / National Institutes of Health, National Institute on Aging (NIH-NIA), Emory University UCLH/UCL Biomedical Centre MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Kronos Science Dementia Unit at South London and Maudsley NHS Foundation Trust MR/L023784/2; G0400713; MC_U106179472; MR/L023784/1; G0300429; MC_U123160651; MC_UU_12015/1; MC_G1000734; MC_UU_12015/2; G0902227 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Stichting MS Research Northern California Institute for Research and Education from GE Healthcare; General Electric Northern California Institute for Research and Education from Novartis AG U24 AG026395; U24 AG026390 / National Institutes of Health, National Institute on Aging (NIH-NIA), NIA LOAD Bristol Research into Alzheimer's and Care of the Elderly R01 AG019085 / National Institutes of Health, National Institute on Aging (NIH-NIA), Vanderbilt University OPTIMA group P30 AG010124 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of Pennsylvania German National Genome Research Network Medical Research Council (MRC); UK Research & Innovation (UKRI); Medical Research Council UK (MRC) IIRG-08-89720 / Alzheimer's Association (LAF); Alzheimer's Association Banner Alzheimer's Foundation P30 AG010161; R01 AG019085; R01 AG15819; R01 AG17917; R01 AG30146 / National Institutes of Health, National Institute on Aging (NIH-NIA), Rush University Northern California Institute for Research and Education from AstraZeneca AB Royal College of Physicians/Dunhill Medical Trust; Dunhill Medical Trust R01 AG031581 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of Arizona P50 AG005681; P01 AG03991 / National Institutes of Health, National Institute on Aging (NIH-NIA), Washington University Barnes Jewish Foundation P50 AG008671 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of Michigan U24 AG021886 / National Institutes of Health, National Institute on Aging (NIH-NIA), NCRAD National Institute of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [Institute of Psychiatry] King's College London; General Electric P50 AG005142 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of Southern California NS39764 / NINDS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) NHS trusts North Bristol NHS Trust Research and Innovation Department P50 AG005133; AG030653; AG041718 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of Pittsburgh IIRG-05-14147 / Alzheimer's Association (MP-V); Alzheimer's Association Wellcome Trust P50 AG005131 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of California, San Diego NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30 AG10133 / National Institutes of Health, National Institute on Aging (NIH-NIA), Indiana University Northern California Institute for Research and Education from Pfizer Inc Northern California Institute for Research and Education from Schering-Plough NF-SI-0512-10033; NF-SI-0512-10135; CL-2011-18-004 / National Institute for Health Research; National Institutes of Health Research (NIHR) AG041232 / NIA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) U01 AG032984; RC2 AG036528 / National Institutes of Health, National Institute on Aging (NIH-NIA), ADGC P30 AG010129 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of California, Davis Northern California Institute for Research and Education from F. Hoffman-La Roche Alzheimer's Society National Institute of Child Health and Human Development; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) R165-2013-15320 / Lundbeck Foundation; Lundbeckfonden 167 / Alzheimer's Society P30 AG08051; MO1RR00096; UL1 RR029893; 5R01AG012101; 5R01AG022374; 5R01AG013616; 1RC2AG036502; 1R01AG035137 / National Institutes of Health, National Institute on Aging (NIH-NIA), New York University Northern California Institute for Research and Education from Eisai Global Clinical Development Canadian Institute of Health Research; Canadian Institutes of Health Research (CIHR) Ulster Garden Villages, N. Ireland RD Office P50 AG023501; P01 AG019724 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of California, San Francisco P50 AG016573; P50 AG016575; P50 AG016576; P50 AG016577 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of California, Irvine Northern California Institute for Research and Education from Eli Lilly and Co. Northern California Institute for Research and Education from Alzheimer's Drug Discovery Foundation NIHR Queen Square Dementia Biomedical Research Unit Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Northern California Institute for Research and Education from Synarc, Inc. Competence Network Dementia Northern California Institute for Research and Education from Bristol-Myers Squibb Northern California Institute for Research and Education from Johnson and Johnson Lundbeck Foundation; Lundbeckfonden Northern California Institute for Research and Education from Abbott P30 AG013846; U01 AG10483; R01 CA129769; R01 MH080295; R01 AG017173; R01 AG025259; R01AG33193 / National Institutes of Health, National Institute on Aging (NIH-NIA), Boston University P50 AG016570 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of California, Los Angeles Munich Center of Health Sciences U01 AG024904; RC2 AG036535; K01 AG030514 / Northern California Institute for Research and Education from NIA Alzheimer's Research UK (ARUK) Intramural Research Program of the National Institute on Aging; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Northern California Institute for Research and Education from Medpace, Inc. BRACE U01 AG 06781 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA ES/L008238/1 / Economic and Social Research Council; UK Research & Innovation (UKRI); Economic & Social Research Council (ESRC) P30 AG019610 / National Institutes of Health, National Institute on Aging (NIH-NIA), Banner Sun Health Research Institute P50 AG016574 / National Institutes of Health, National Institute on Aging (NIH-NIA), Mayo Clinic Welsh Assembly Government Howard Hughes Medical Institute German Federal Ministry of Education and Research (BMBF); Federal Ministry of Education & Research (BMBF) LSHM_CT_2006_037197 / EU; European Commission P50 AG005134 / National Institutes of Health, National Institute on Aging (NIH-NIA), Massachusetts General Hospital; General Electric Higher Education Funding Council for England (HEFCE); UK Research & Innovation (UKRI) International Parkinson Fonds U01 AG06781; U01 HG004610; U01 HG006375 / National Institutes of Health, National Institute on Aging (NIH-NIA), Group Health Research Institute Helmholtz Zentrum Munchen; Helmholtz Association 115372 / Innovative Medicines Initiative Joint Undertaking under EMIF R01 AG027944; AG010491; AG027944; AG021547; AG019757 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of Miami BMBF; Federal Ministry of Education & Research (BMBF) Trinity College group P50 AG005146; R01 AG020688 / National Institutes of Health, National Institute on Aging (NIH-NIA), Johns Hopkins University Internationale Stiching Alzheimer Onderzoek MC_UU_12015/2; G0300429; MC_UU_12015/1; G0400713; MC_U106179472; MR/L501529/1; MC_U123160651; MC_U106179471; MR/L023784/2; G0902227; MR/L023784/1; MR/L010305/1; MR/K006584/1; MC_PC_13048 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Alfried Krupp von Bohlen und Halbach-Stiftung P50 AG005136 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of Washington state of Arizona German Research Center for Environmental Health Northern California Institute for Research and Education from Genentech NINDS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) P30 AG013854 / National Institutes of Health, National Institute on Aging (NIH-NIA), Northwestern University P30 AG028383; AG05144 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of Kentucky P50 AG016582; UL1RR02777 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of Alabama at Birmingham P30 AG028377; AG05128 / National Institutes of Health, National Institute on Aging (NIH-NIA), Duke University Northern California Institute for Research and Education from Bayer Schering Pharma AG Newcastle University Northern California Institute for Research and Education from Alzheimer's Association US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program Juvenile Diabetes Research Foundation International; Juvenile Diabetes Research Foundation Northern California Institute for Research and Education from Merck and Co., Inc. Charles and Joanne Knight Alzheimer's Research Initiative P30 AG008017; R01 AG026916 / National Institutes of Health, National Institute on Aging (NIH-NIA), Oregon Health & Science University National Human Genome Research Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) Competence Network Degenerative Dementia Johnnie B. Byrd Sr. Alzheimer's Institute Northern California Institute for Research and Education from Innogenetics Northern California Institute for Research and Education from GlaxoSmithKline National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre ARUK-NCG2014A-1; ARUK-PG2014-2 / Alzheimers Research UK; Alzheimer's Research UK (ARUK) P50 AG008702; R37 AG015473 / National Institutes of Health, National Institute on Aging (NIH-NIA), Columbia University Hersenstichting Nederland Breinbrekend Werk P30 AG012300 / National Institutes of Health, National Institute on Aging (NIH-NIA), University of Texas Southwestern MH60451 / NIMH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) Northern California Institute for Research and Education from Dana Foundation Lundbeck SA; Lundbeck Corporation DeNDRoN P50 AG005138; P01 AG002219 / National Institutes of Health, National Institute on Aging (NIH-NIA), Mount Sinai School of Medicine U01 AG016976 / National Institutes of Health, National Institute on Aging (NIH-NIA), NACC Northern California Institute for Research and Education from National Institute of Biomedical Imaging and Bioengineering ES/L008238/1 / ESRC; UK Research & Innovation (UKRI); Economic & Social Research Council (ESRC) Brain Net Europe National Institute of Allergy and Infectious Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) Alzheimer's Research Trust (ART)
Identifiers: 9936171708331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article