Genetically predicted body mass index and Alzheimer's disease-related phenotypes in three large samples: Mendelian randomization analyses

doi:10.1016/j.jalz.2015.05.015

Genetically predicted body mass index and Alzheimer's disease-related phenotypes in three large samples: Mendelian randomization analyses

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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	https://doi.org/10.1016/j.jalz.2015.05.015
State	Published - Dec 1 2015

Bibliographical note

Publisher Copyright:
© 2015 The Alzheimer's Association.

Funding

ACT: ACT is supported by a grant ( U01 AG 06781 , to E.B.L. and P.K.C.) from the National Institutes of Health . 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. ROS/MAP: ROS and MAP are supported by National Institute on Aging grants R01AG17917 , R01AG34374 , R01AG15819 , and P30AG10161 (all to D.A.B.).

Funders	Funder number
National Institutes of Health (NIH)
Michigan Retirement Research Center, University of Michigan
National Institute on Aging	P50AG005144, R01AG033193, P50AG005146, RC2AG036535, RF1AG015819, P50AG005142, R01AG035137, RC2AG036495, U24AG021886, U01AG024904, R01AG019085, R01AG025259, U01AG016976, P01AG010491, R01AG013616, P50AG005133, RC2AG036528, R01AG012101, P50AG005134, P50AG005131, R01AG054060, U01AG009740, R01AG019771, K01AG030514, P30AG013854, P30AG028383, R01AG027944, P50AG016582, U01AG010483, P50AG005136, R01AG022374, P50AG025688, P50AG023501, R01AG041232, R01AG008122, P50AG005138, R01AG041797, R01AG021547, P50AG008671, P50AG005681, P30AG028377, R01AG041718, R37AG015473, R01AG026916, P01AG019724, R01AG030146, U01AG006781, P50AG016573, P50AG016574, RC4AG039029, P30AG013846, P30AG010133, R01AG030653, P50AG016570, R01AG017917, P50AG005128, P01AG002219, U01AG032984, R01AG042611, RC2AG036502, R43AG051285, R01AG026390, R01AG019757, R01AG020688, R01AG017173, R01AG031581, P30AG008017, R01AG034374, U24AG026395, P30AG010124, P30AG012300, P30AG010161, P01AG003991, P30AG010129, P30AG019610, P30AG008051, P50AG008702
National Institute on Aging
National Institute of Mental Health	P50MH060451, R01MH080295
National Institute of Mental Health
National Institute on Alcohol Abuse and Alcoholism	R01AA023416
National Institute on Alcohol Abuse and Alcoholism
National Center for Advancing Translational Sciences (NCATS)	UL1TR001445, UL1TR001108, UL1TR002529
National Center for Advancing Translational Sciences (NCATS)
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01NS059873, P50NS039764
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council
U.S. Department of Veterans Affairs	IK2BX001820
U.S. Department of Veterans Affairs
National Human Genome Research Institute	U01HG006375, U01HG004610
National Human Genome Research Institute
National Childhood Cancer Registry – National Cancer Institute	R01CA129769
National Childhood Cancer Registry – National Cancer Institute
National Center for Research Resources	M01RR000096, UL1RR029893
National Center for Research Resources

Keywords

Alzheimer's disease
Dementia
Mendelian randomization
Obesity

ASJC Scopus subject areas

Epidemiology
Health Policy
Developmental Neuroscience
Clinical Neurology
Geriatrics and Gerontology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jalz.2015.05.015

Cite this

@article{c0cff54ffdd942f49cde973061b77b54,

title = "Genetically predicted body mass index and Alzheimer's disease-related phenotypes in three large samples: Mendelian randomization analyses",

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.",

keywords = "Alzheimer's disease, Dementia, Mendelian randomization, Obesity",

author = "Shubhabrata Mukherjee and Stefan Walter and Kauwe, \{John S.K.\} and Saykin, \{Andrew J.\} and Bennett, \{David A.\} and Larson, \{Eric B.\} and Crane, \{Paul K.\} and Glymour, \{M. Maria\} and Albert, \{Marilyn S.\} and Albin, \{Roger L.\} and Apostolova, \{Liana G.\} and Arnold, \{Steven E.\} and Sanjay Asthana and Atwood, \{Craig S.\} and Baldwin, \{Clinton T.\} and Barber, \{Robert C.\} and Barmada, \{Michael M.\} and Barnes, \{Lisa L.\} and Beach, \{Thomas G.\} and Becker, \{James T.\} and Beecham, \{Gary W.\} and Duane Beekly and Bigio, \{Eileen H.\} and Bird, \{Thomas D.\} and Deborah Blacker and Boeve, \{Bradley F.\} and Bowen, \{James D.\} and Adam Boxer and Burke, \{James R.\} and Buxbaum, \{Joseph D.\} and Cairns, \{Nigel J.\} and Cantwell, \{Laura B.\} and Chuanhai Cao and Carlson, \{Chris S.\} and Carlsson, \{Cynthia M.\} and Carney, \{Regina M.\} and Carrasquillo, \{Minerva M.\} and Carroll, \{Steven L.\} and Chui, \{Helena C.\} and Clark, \{David G.\} and Jason Corneveaux and Cribbs, \{David H.\} and Crocco, \{Elizabeth A.\} and Carlos Cruchaga and \{De Jager\}, \{Philip L.\} and Charles DeCarli and Demirci, \{F. Yesim\} and Malcolm Dick and Jicha, \{Gregory A.\} and \{Van Eldik\}, \{Linda J.\}",

note = "Publisher Copyright: {\textcopyright} 2015 The Alzheimer's Association.",

year = "2015",

month = dec,

day = "1",

doi = "10.1016/j.jalz.2015.05.015",

language = "English",

volume = "11",

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T2 - Mendelian randomization analyses

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 - Jicha, Gregory A.

AU - Van Eldik, Linda J.

PY - 2015/12/1

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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

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SN - 1552-5260

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JO - Alzheimer's and Dementia

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Genetically predicted body mass index and Alzheimer's disease-related phenotypes in three large samples: Mendelian randomization analyses

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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