Exploratory analysis of mtDNA haplogroups in two Alzheimer's longitudinal cohorts

Russell H. Swerdlow; Dongwei Hui; Prabhakar Chalise; Palash Sharma; Xinkun Wang; Shea J. Andrews; Judy Pa; Jonathan D. Mahnken; Jill Morris; Heather M. Wilkins; Jeffrey M. Burns; Mary L. Michaelis; Elias K. Michaelis

doi:10.1002/alz.12119

Exploratory analysis of mtDNA haplogroups in two Alzheimer's longitudinal cohorts

Russell H. Swerdlow^*, Dongwei Hui, Prabhakar Chalise, Palash Sharma, Xinkun Wang, Shea J. Andrews, Judy Pa, Jonathan D. Mahnken, Jill Morris, Heather M. Wilkins, Jeffrey M. Burns, Mary L. Michaelis, Elias K. Michaelis

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Introduction: Inherited mitochondrial DNA (mtDNA) variants may influence Alzheimer's disease (AD) risk. Methods: We sequenced mtDNA from 146 AD and 265 cognitively normal (CN) subjects from the University of Kansas AD Center (KUADC) and assigned haplogroups. We further considered 244 AD and 242 CN AD Neuroimaging Initiative (ADNI) subjects with equivalent data. Results: Without applying multiple comparisons corrections, KUADC haplogroup J AD and CN frequencies were 16.4% versus 7.6% (P =.007), and haplogroup K AD and CN frequencies were 4.8% versus 10.2% (P =.063). ADNI haplogroup J AD and CN frequencies were 10.7% versus 7.0% (P =.20), and haplogroup K frequencies were 4.9% versus 8.7% (P =.11). For the combined 390 AD and 507 CN cases haplogroup J frequencies were 12.8% versus 7.3% (P =.006), odds ratio (OR) = 1.87, and haplogroup K frequencies were 4.9% versus 9.5% (P =.010), OR = 0.49. Associations remained significant after adjusting for apolipoprotein E, age, and sex. Conclusion: This exploratory analysis suggests inherited mtDNA variants influence AD risk.

Original language	English (US)
Pages (from-to)	1164-1172
Number of pages	9
Journal	Alzheimer's and Dementia
Volume	16
Issue number	8
DOIs	https://doi.org/10.1002/alz.12119
State	Published - Aug 1 2020

Funding

This work was supported by National Institute on Aging funding to the University of Kansas Alzheimer's Disease Center (P30AG035982). This work was also partially supported through UL1 TR002366. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; 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.; Cogstate; 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This work was supported by National Institute on Aging funding to the University of Kansas Alzheimer's Disease Center (P30AG035982). This work was also partially supported through UL1 TR002366. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; 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.; Cogstate; 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Keywords

Alzheimer's disease
apolipoprotein E
haplogroup
mitochondria
mitochondrial DNA

ASJC Scopus subject areas

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

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10.1002/alz.12119

Cite this

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title = "Exploratory analysis of mtDNA haplogroups in two Alzheimer's longitudinal cohorts",

abstract = "Introduction: Inherited mitochondrial DNA (mtDNA) variants may influence Alzheimer's disease (AD) risk. Methods: We sequenced mtDNA from 146 AD and 265 cognitively normal (CN) subjects from the University of Kansas AD Center (KUADC) and assigned haplogroups. We further considered 244 AD and 242 CN AD Neuroimaging Initiative (ADNI) subjects with equivalent data. Results: Without applying multiple comparisons corrections, KUADC haplogroup J AD and CN frequencies were 16.4% versus 7.6% (P =.007), and haplogroup K AD and CN frequencies were 4.8% versus 10.2% (P =.063). ADNI haplogroup J AD and CN frequencies were 10.7% versus 7.0% (P =.20), and haplogroup K frequencies were 4.9% versus 8.7% (P =.11). For the combined 390 AD and 507 CN cases haplogroup J frequencies were 12.8% versus 7.3% (P =.006), odds ratio (OR) = 1.87, and haplogroup K frequencies were 4.9% versus 9.5% (P =.010), OR = 0.49. Associations remained significant after adjusting for apolipoprotein E, age, and sex. Conclusion: This exploratory analysis suggests inherited mtDNA variants influence AD risk.",

keywords = "Alzheimer's disease, apolipoprotein E, haplogroup, mitochondria, mitochondrial DNA",

author = "Swerdlow, {Russell H.} and Dongwei Hui and Prabhakar Chalise and Palash Sharma and Xinkun Wang and Andrews, {Shea J.} and Judy Pa and Mahnken, {Jonathan D.} and Jill Morris and Wilkins, {Heather M.} and Burns, {Jeffrey M.} and Michaelis, {Mary L.} and Michaelis, {Elias K.}",

note = "Funding Information: This work was supported by National Institute on Aging funding to the University of Kansas Alzheimer's Disease Center (P30AG035982). This work was also partially supported through UL1 TR002366. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; 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.; Cogstate; 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: This work was supported by National Institute on Aging funding to the University of Kansas Alzheimer's Disease Center (P30AG035982). This work was also partially supported through UL1 TR002366. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; 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.; Cogstate; 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Publisher Copyright: {\textcopyright} 2020 the Alzheimer's Association",

year = "2020",

month = aug,

day = "1",

doi = "10.1002/alz.12119",

language = "English (US)",

volume = "16",

pages = "1164--1172",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc.",

number = "8",

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TY - JOUR

T1 - Exploratory analysis of mtDNA haplogroups in two Alzheimer's longitudinal cohorts

AU - Swerdlow, Russell H.

AU - Hui, Dongwei

AU - Chalise, Prabhakar

AU - Sharma, Palash

AU - Wang, Xinkun

AU - Andrews, Shea J.

AU - Pa, Judy

AU - Mahnken, Jonathan D.

AU - Morris, Jill

AU - Wilkins, Heather M.

AU - Burns, Jeffrey M.

AU - Michaelis, Mary L.

AU - Michaelis, Elias K.

N1 - Funding Information: This work was supported by National Institute on Aging funding to the University of Kansas Alzheimer's Disease Center (P30AG035982). This work was also partially supported through UL1 TR002366. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; 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.; Cogstate; 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: This work was supported by National Institute on Aging funding to the University of Kansas Alzheimer's Disease Center (P30AG035982). This work was also partially supported through UL1 TR002366. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; 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.; Cogstate; 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Publisher Copyright: © 2020 the Alzheimer's Association

PY - 2020/8/1

Y1 - 2020/8/1

N2 - Introduction: Inherited mitochondrial DNA (mtDNA) variants may influence Alzheimer's disease (AD) risk. Methods: We sequenced mtDNA from 146 AD and 265 cognitively normal (CN) subjects from the University of Kansas AD Center (KUADC) and assigned haplogroups. We further considered 244 AD and 242 CN AD Neuroimaging Initiative (ADNI) subjects with equivalent data. Results: Without applying multiple comparisons corrections, KUADC haplogroup J AD and CN frequencies were 16.4% versus 7.6% (P =.007), and haplogroup K AD and CN frequencies were 4.8% versus 10.2% (P =.063). ADNI haplogroup J AD and CN frequencies were 10.7% versus 7.0% (P =.20), and haplogroup K frequencies were 4.9% versus 8.7% (P =.11). For the combined 390 AD and 507 CN cases haplogroup J frequencies were 12.8% versus 7.3% (P =.006), odds ratio (OR) = 1.87, and haplogroup K frequencies were 4.9% versus 9.5% (P =.010), OR = 0.49. Associations remained significant after adjusting for apolipoprotein E, age, and sex. Conclusion: This exploratory analysis suggests inherited mtDNA variants influence AD risk.

AB - Introduction: Inherited mitochondrial DNA (mtDNA) variants may influence Alzheimer's disease (AD) risk. Methods: We sequenced mtDNA from 146 AD and 265 cognitively normal (CN) subjects from the University of Kansas AD Center (KUADC) and assigned haplogroups. We further considered 244 AD and 242 CN AD Neuroimaging Initiative (ADNI) subjects with equivalent data. Results: Without applying multiple comparisons corrections, KUADC haplogroup J AD and CN frequencies were 16.4% versus 7.6% (P =.007), and haplogroup K AD and CN frequencies were 4.8% versus 10.2% (P =.063). ADNI haplogroup J AD and CN frequencies were 10.7% versus 7.0% (P =.20), and haplogroup K frequencies were 4.9% versus 8.7% (P =.11). For the combined 390 AD and 507 CN cases haplogroup J frequencies were 12.8% versus 7.3% (P =.006), odds ratio (OR) = 1.87, and haplogroup K frequencies were 4.9% versus 9.5% (P =.010), OR = 0.49. Associations remained significant after adjusting for apolipoprotein E, age, and sex. Conclusion: This exploratory analysis suggests inherited mtDNA variants influence AD risk.

KW - Alzheimer's disease

KW - apolipoprotein E

KW - haplogroup

KW - mitochondria

KW - mitochondrial DNA

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Exploratory analysis of mtDNA haplogroups in two Alzheimer's longitudinal cohorts

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