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

Søren D Østergaard; 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

doi:10.1371/journal.pmed.1001841

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

Journal article

Open access

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

Søren D Østergaard, 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

2015-06

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

PMCID: PMC4469461

PMID: 26079503

Appears in UM Open Access Research Published in PloS

Abstract

Genetic Predisposition to Disease

Humans

Risk Factors

Mendelian Randomization Analysis

Female

Male

Polymorphism, Single Nucleotide

Alzheimer Disease - genetics

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). We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 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 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 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 × 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. 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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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.60 Dementia
Web Of Science research areas: Genetics & Heredity
ESI research areas: Clinical Medicine

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Title: Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study
Creators: Søren D Østergaard - Research Department P, Aarhus University Hospital, Risskov, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Shubhabrata Mukherjee - Department of Medicine, University of Washington, Seattle, Washington, United States of America
Stephen J Sharp - MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
Petroula Proitsi - Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom
Luca A Lotta - MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
Felix Day - MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
John R B Perry - MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
Kevin L Boehme - Department of Biology, Brigham Young University, Provo, Utah, United States of America
Stefan Walter - Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, California, United States of America
John S Kauwe - Department of Biology, Brigham Young University, Provo, Utah, United States of America
Laura E Gibbons - Department of Medicine, University of Washington, Seattle, Washington, United States of America
Eric B Larson - Department of Medicine, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Seattle, Washington, United States of America
John F Powell - Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom
Claudia Langenberg - MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
Paul K Crane - Department of Medicine, University of Washington, Seattle, Washington, United States of America
Nicholas J Wareham - MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
Robert A Scott - MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
Publication Details: PLoS medicine, Vol.12(6), pp.e1001841; discussion e1001841-e1001841; discussion e1001841
Publisher: United States
Grant note: P30 AG062421 / NIA NIH HHS P30 AG028377 / NIA NIH HHS P50 NS039764 / NINDS NIH HHS P50 AG005144 / NIA NIH HHS R01 AG027944 / NIA NIH HHS MR/L023784/1 / Medical Research Council R01 AG030146 / NIA NIH HHS MC_G1000734 / Medical Research Council P50 MH060451 / NIMH NIH HHS U54 CA132378 / NCI NIH HHS P50 AG008702 / NIA NIH HHS P50 AG023501 / NIA NIH HHS R37 AG015473 / NIA NIH HHS P01 AG010491 / NIA NIH HHS Intramural NIH HHS P50 AG005681 / NIA NIH HHS P30 AG008017 / NIA NIH HHS R01 AG031581 / NIA NIH HHS R01 AG019085 / NIA NIH HHS AG05144 / NIA NIH HHS 5R01AG012101 / NIA NIH HHS P01 AG03991 / NIA NIH HHS R01 AG030653 / NIA NIH HHS 5R01AG022374 / NIA NIH HHS R01 AG021547 / NIA NIH HHS P50 AG016573 / NIA NIH HHS P01 AG019724 / NIA NIH HHS MC_U106179472 / Medical Research Council U24 AG026390 / NIA NIH HHS MC_UU_12015/2 / Medical Research Council UL1RR02777 / NCRR NIH HHS K01 AG030514 / NIA NIH HHS R01 MH080295 / NIMH NIH HHS P50 AG005134 / NIA NIH HHS P50 AG005128 / NIA NIH HHS AG041232 / NIA NIH HHS MR/L023784/2 / Medical Research Council Wellcome Trust MH60451 / NIMH NIH HHS P50 AG016575 / NIA NIH HHS NS39764 / NINDS NIH HHS MR/L501529/1 / Medical Research Council R01 CA129769 / NCI NIH HHS R01 AG035137 / NIA NIH HHS P30 AG08051 / NIA NIH HHS 167 / Alzheimer's Society MC_U106179471 / Medical Research Council P30 AG010129 / NIA NIH HHS R01 AG020688 / NIA NIH HHS AG041718 / NIA NIH HHS R01 AG022374 / NIA NIH HHS R01 AG026916 / NIA NIH HHS P50 AG005142 / NIA NIH HHS G0400713 / Medical Research Council R01 NS059873 / NINDS NIH HHS P30 AG010124 / NIA NIH HHS U24 AG026395 / NIA NIH HHS R01 AG17917 / NIA NIH HHS U01 AG016976 / NIA NIH HHS U01 AG 06781 / NIA NIH HHS U24 AG021886 / NIA NIH HHS R01 AG017917 / NIA NIH HHS P30 AG008051 / NIA NIH HHS 081864 / Wellcome Trust U01 AG032984 / NIA NIH HHS P50 AG016574 / NIA NIH HHS U01 AG006781 / NIA NIH HHS P50 AG008671 / NIA NIH HHS R01 AG019757 / NIA NIH HHS P30 ES013508 / NIEHS NIH HHS R01 AG30146 / NIA NIH HHS RC2 AG036528 / NIA NIH HHS MO1RR00096 / NCRR NIH HHS R01 AG041232 / NIA NIH HHS Howard Hughes Medical Institute R01 AG041718 / NIA NIH HHS P50 AG005131 / NIA NIH HHS R01 AG042611 / NIA NIH HHS M01 RR000096 / NCRR NIH HHS P30 AG019610 / NIA NIH HHS P50 AG016576 / NIA NIH HHS P01 AG002219 / NIA NIH HHS UL1 TR001445 / NCATS NIH HHS P50 AG005136 / NIA NIH HHS U01 AG024904 / NIA NIH HHS U01 HG008657 / NHGRI NIH HHS MR/L010305/1 / Medical Research Council 1R01AG035137 / NIA NIH HHS R01AG33193 / NIA NIH HHS 5R01AG013616 / NIA NIH HHS AG021547 / NIA NIH HHS U01 HG006375 / NHGRI NIH HHS MC_UU_12015/1 / Medical Research Council P50 AG005146 / NIA NIH HHS AG030653 / NIA NIH HHS RC2 AG036535 / NIA NIH HHS MR/K006584/1 / Medical Research Council R01 AG011101 / NIA NIH HHS P50 AG016582 / NIA NIH HHS P50 AG016570 / NIA NIH HHS U01 HG004610 / NHGRI NIH HHS P30 AG010161 / NIA NIH HHS P30 AG013854 / NIA NIH HHS AG027944 / NIA NIH HHS R01 AG012101 / NIA NIH HHS R01 AG017173 / NIA NIH HHS R01 AG015819 / NIA NIH HHS P30 AG10133 / NIA NIH HHS 1RC2AG036502 / NIA NIH HHS U01 AG06781 / NIA NIH HHS U01 AG10483 / NIA NIH HHS MC_U123160651 / Medical Research Council AG05128 / NIA NIH HHS R01 AG033193 / NIA NIH HHS R01 AG15819 / NIA NIH HHS AG010491 / NIA NIH HHS AG019757 / NIA NIH HHS UL1 TR001108 / NCATS NIH HHS U01 AG010483 / NIA NIH HHS 089703 / Wellcome Trust P30 AG028383 / NIA NIH HHS P30 AG012300 / NIA NIH HHS P30 AG010133 / NIA NIH HHS P50 AG005133 / NIA NIH HHS R01 AG013616 / NIA NIH HHS P50 AG025688 / NIA NIH HHS P01 AG003991 / NIA NIH HHS G0300429 / Medical Research Council CIHR P30 AG013846 / NIA NIH HHS R01 AG025259 / NIA NIH HHS AG025688 / NIA NIH HHS P50 AG005138 / NIA NIH HHS UL1 RR029893 / NCRR NIH HHS P50 AG016577 / NIA NIH HHS R01 AG026390 / NIA NIH HHS G0902227 / Medical Research Council RC2 AG036502 / NIA NIH HHS
Language: English
Resource Type: Journal article
PMID: 26079503
PMCID: PMC4469461
Record Identifier: 991031577539302976