Abstract
Observational research shows that higher body mass index (BMI) increases Alzheimer's disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. We evaluated individual-level data from the AD Genetics Consortium (ADGC: 10,079 AD cases and 9613 controls), the Health and Retirement Study (HRS: 8403 participants with algorithm-predicted dementia status), and published associations from the Genetic and Environmental Risk for AD consortium (GERAD1: 3177 AD cases and 7277 controls). No evidence from individual single-nucleotide polymorphisms or polygenic scores indicated BMI increased AD risk. Mendelian randomization effect estimates per BMI point (95% confidence intervals) were as follows: ADGC, odds ratio (OR) = 0.95 (0.90-1.01); HRS, OR = 1.00 (0.75-1.32); GERAD1, OR = 0.96 (0.87-1.07). One subscore (cellular processes not otherwise specified) unexpectedly predicted lower AD risk.
| Original language | English |
|---|---|
| Pages (from-to) | 1439-1451 |
| Number of pages | 13 |
| Journal | Alzheimer's and Dementia |
| Volume | 11 |
| Issue number | 12 |
| DOIs | |
| State | Published - 1 Dec 2015 |
Keywords
- Alzheimer's disease
- Dementia
- Mendelian randomization
- Obesity
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Genetically predicted body mass index and Alzheimer's disease-related phenotypes in three large samples : Mendelian randomization analyses. / Adult Changes in Thought Study Investigators; Religious Orders Study/Memory and Aging Project Investigators; Alzheimer's Disease Genetics Consortium.
In: Alzheimer's and Dementia, Vol. 11, No. 12, 01.12.2015, p. 1439-1451.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Genetically predicted body mass index and Alzheimer's disease-related phenotypes in three large samples
T2 - Mendelian randomization analyses
AU - Adult Changes in Thought Study Investigators
AU - Religious Orders Study/Memory and Aging Project Investigators
AU - Alzheimer's Disease Genetics Consortium
AU - Mukherjee, Shubhabrata
AU - Walter, Stefan
AU - Kauwe, John S.K.
AU - Saykin, Andrew J.
AU - Bennett, David A.
AU - Larson, Eric B.
AU - Crane, Paul K.
AU - Glymour, M. Maria
AU - Albert, Marilyn S.
AU - Albin, Roger L.
AU - Apostolova, Liana G.
AU - Arnold, Steven E.
AU - Asthana, Sanjay
AU - Atwood, Craig S.
AU - Baldwin, Clinton T.
AU - Barber, Robert C.
AU - Barmada, Michael M.
AU - Barnes, Lisa L.
AU - Beach, Thomas G.
AU - Becker, James T.
AU - Beecham, Gary W.
AU - Beekly, Duane
AU - Bigio, Eileen H.
AU - Bird, Thomas D.
AU - Blacker, Deborah
AU - Boeve, Bradley F.
AU - Bowen, James D.
AU - Boxer, Adam
AU - Burke, James R.
AU - Buxbaum, Joseph D.
AU - Cairns, Nigel J.
AU - Cantwell, Laura B.
AU - Cao, Chuanhai
AU - Carlson, Chris S.
AU - Carlsson, Cynthia M.
AU - Carney, Regina M.
AU - Carrasquillo, Minerva M.
AU - Carroll, Steven L.
AU - Chui, Helena C.
AU - Clark, David G.
AU - Corneveaux, Jason
AU - Cribbs, David H.
AU - Crocco, Elizabeth A.
AU - Cruchaga, Carlos
AU - De Jager, Philip L.
AU - DeCarli, Charles
AU - Demirci, F. Yesim
AU - Dick, Malcolm
AU - Dickson, Dennis W.
AU - Duara, Ranjan
N1 - Funding Information: The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC , U01 AG032984 , RC2 AG036528 ; NACC , U01 AG016976 ; NCRAD , U24 AG021886 ; NIA LOAD , U24 AG026395 , U24 AG026390 ; Banner Sun Health Research Institute P30 AG019610 ; Boston University , P30 AG013846 , U01 AG10483 , R01 CA129769 , R01 MH080295 , R01 AG017173 , R01 AG025259 , R01AG33193 ; Columbia University , P50 AG008702 , R37 AG015473 ; Duke University , P30 AG028377 , AG05128 ; Emory University , AG025688 ; Group Health Research Institute , U01 AG06781 , U01 HG004610 , U01 HG006375 ; Indiana University , P30 AG10133 ; Johns Hopkins University , P50 AG005146 , R01 AG020688 ; Massachusetts General Hospital , P50 AG005134 ; Mayo Clinic , P50 AG016574 ; Mount Sinai School of Medicine , P50 AG005138 , P01 AG002219 ; New York University , P30 AG08051 , MO1RR00096 , UL1 RR029893 , 5R01AG012101 , 5R01AG022374 , 5R01AG013616 , 1RC2AG036502 , 1R01AG035137 ; Northwestern University , P30 AG013854 ; Oregon Health & Science University , P30 AG008017 , R01 AG026916 ; Rush University , P30 AG010161 , R01 AG019085 , R01 AG15819 , R01 AG17917 , R01 AG30146 ; TGen , R01 NS059873 ; University of Alabama at Birmingham , P50 AG016582 , UL1RR02777 ; University of Arizona , R01 AG031581 ; University of California, Davis , P30 AG010129 ; University of California, Irvine , P50 AG016573 , P50, P50 AG016575 , P50 AG016576 , P50 AG016577 ; University of California, Los Angeles , P50 AG016570 ; University of California, San Diego , P50 AG005131 ; University of California, San Francisco , P50 AG023501 , P01 AG019724 ; University of Kentucky , P30 AG028383 , AG05144 ; University of Michigan , P50 AG008671 ; University of Pennsylvania , P30 AG010124 ; University of Pittsburgh , P50 AG005133 , AG030653 , AG041718 ; University of Southern California , P50 AG005142 ; University of Texas Southwestern , P30 AG012300 ; University of Miami , R01 AG027944 , AG010491 , AG027944 , AG021547 , AG019757 ; University of Washington , P50 AG005136 ; Vanderbilt University , R01 AG019085 ; and Washington University , P50 AG005681 , P01 AG03991 . The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant numbers NS39764 , NIMH MH60451 and by GlaxoSmithKline . Genotyping of the TGEN2 cohort was supported by Kronos Science . The TGen series was also funded by NIA grant AG041232 to A.J.M. and M.J.H., The Banner Alzheimer's Foundation , The Johnnie B. Byrd Sr. Alzheimer's Institute , the Medical Research Council , and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts, and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer's Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI Data collection and sharing for this project was funded by the (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex officio ADGC members. Support was also from the Alzheimer's Association (L.A.F., IIRG-08-89720 ; M.P.-V., IIRG-05-14147 ) and the US Department of Veterans Affairs Administration , Office of Research and Development, Biomedical Laboratory Research Program. P.S.G.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. Funding Information: ACT: ACT is supported by a grant ( U01 AG 06781 , to E.B.L. and P.K.C.) from the National Institutes of Health . Funding Information: ROS/MAP: ROS and MAP are supported by National Institute on Aging grants R01AG17917 , R01AG34374 , R01AG15819 , and P30AG10161 (all to D.A.B.). Funding Information: The Health and Retirement Study genetic data are sponsored by the National Institute on Aging (grant numbers U01AG009740 , RC2AG036495 , and RC4AG039029 ) and was conducted by the University of Michigan. Publisher Copyright: © 2015 The Alzheimer's Association.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - Observational research shows that higher body mass index (BMI) increases Alzheimer's disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. We evaluated individual-level data from the AD Genetics Consortium (ADGC: 10,079 AD cases and 9613 controls), the Health and Retirement Study (HRS: 8403 participants with algorithm-predicted dementia status), and published associations from the Genetic and Environmental Risk for AD consortium (GERAD1: 3177 AD cases and 7277 controls). No evidence from individual single-nucleotide polymorphisms or polygenic scores indicated BMI increased AD risk. Mendelian randomization effect estimates per BMI point (95% confidence intervals) were as follows: ADGC, odds ratio (OR) = 0.95 (0.90-1.01); HRS, OR = 1.00 (0.75-1.32); GERAD1, OR = 0.96 (0.87-1.07). One subscore (cellular processes not otherwise specified) unexpectedly predicted lower AD risk.
AB - Observational research shows that higher body mass index (BMI) increases Alzheimer's disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. We evaluated individual-level data from the AD Genetics Consortium (ADGC: 10,079 AD cases and 9613 controls), the Health and Retirement Study (HRS: 8403 participants with algorithm-predicted dementia status), and published associations from the Genetic and Environmental Risk for AD consortium (GERAD1: 3177 AD cases and 7277 controls). No evidence from individual single-nucleotide polymorphisms or polygenic scores indicated BMI increased AD risk. Mendelian randomization effect estimates per BMI point (95% confidence intervals) were as follows: ADGC, odds ratio (OR) = 0.95 (0.90-1.01); HRS, OR = 1.00 (0.75-1.32); GERAD1, OR = 0.96 (0.87-1.07). One subscore (cellular processes not otherwise specified) unexpectedly predicted lower AD risk.
KW - Alzheimer's disease
KW - Dementia
KW - Mendelian randomization
KW - Obesity
UR - http://www.scopus.com/inward/record.url?scp=84952308113&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2015.05.015
DO - 10.1016/j.jalz.2015.05.015
M3 - Article
C2 - 26079416
AN - SCOPUS:84952308113
VL - 11
SP - 1439
EP - 1451
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
IS - 12
ER -