TY - JOUR
T1 - Mitonuclear interactions influence Alzheimer's disease risk
AU - Alzheimer's Disease Neuroimaging Initiative
AU - Andrews, Shea J.
AU - Fulton-Howard, Brian
AU - Patterson, Christopher
AU - McFall, G. Peggy
AU - Gross, Alden
AU - Michaelis, Elias K.
AU - Goate, Alison
AU - Swerdlow, Russell H.
AU - Pa, Judy
N1 - Funding Information:
Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative, United States (National Institutes of Health, United States Grant U01 AG024904) and DOD ADNI (Department of Defense, United States award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, United States, 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 study was conducted as a part of the 2017 Advanced Psychometric Methods in Cognitive Aging Research conference supported by the National Institute on Aging (R13AG030995; PI: Dan Mungas). JP and CP were supported by the National Institute on Aging (R01AG054617 PI: JP). SJA, BF-H, and AMG are supported by the JPB Foundation, United States (http://www.jpbfoundation.org). EKM and RHS are supported by the National Institute on Aging (P30AG035982).
Funding Information:
Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative , United States ( National Institutes of Health , United States Grant U01 AG024904 ) and DOD ADNI ( Department of Defense , United States award number W81XWH-12-2-0012 ). ADNI is funded by the National Institute on Aging, United States, 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 study was conducted as a part of the 2017 Advanced Psychometric Methods in Cognitive Aging Research conference supported by the National Institute on Aging ( R13AG030995 ; PI: Dan Mungas). JP and CP were supported by the National Institute on Aging ( R01AG054617 PI: JP). SJA, BF-H, and AMG are supported by the JPB Foundation , United States ( http://www.jpbfoundation.org ). EKM and RHS are supported by the National Institute on Aging ( P30AG035982 ). Appendix A
Publisher Copyright:
© 2019 The Author(s)
PY - 2020/3
Y1 - 2020/3
N2 - We examined the associations between mitochondrial DNA haplogroups (MT-hgs; mitochondrial haplotype groups defined by a specific combination of single nucleotide polymorphisms labeled as letters running from A to Z) and their interactions with a polygenic risk score composed of nuclear-encoded mitochondrial genes (nMT-PRS) with risk of dementia and age of onset (AOO) of dementia. MT-hg K (Odds ratio [OR]: 2.03 [95% CI: 1.04, 3.97]) and a 1 SD larger nMT-PRS (OR: 2.2 [95% CI: 1.68, 2.86]) were associated with elevated odds of dementia. Significant antagonistic interactions between the nMT-PRS and MT-hg K (OR: 0.45 [95% CI: 0.22, 0.9]) and MT-hg T (OR: 0.22 [95% CI: 0.1, 0.49]) were observed. Individual MT-hgs were not associated with AOO; however, a significant antagonistic interactions was observed between the nMT-PRS and MT-hg T (Hazard ratio: 0.62 [95% CI: 0.42, 0.91]) and a synergistic interaction between the nMT-PRS and MT-hg V (Hazard ratio: 2.28 [95% CI: 1.19, 4.35]). These results suggest that MT-hgs influence dementia risk and that variants in the nuclear and mitochondrial genome interact to influence the AOO of dementia.
AB - We examined the associations between mitochondrial DNA haplogroups (MT-hgs; mitochondrial haplotype groups defined by a specific combination of single nucleotide polymorphisms labeled as letters running from A to Z) and their interactions with a polygenic risk score composed of nuclear-encoded mitochondrial genes (nMT-PRS) with risk of dementia and age of onset (AOO) of dementia. MT-hg K (Odds ratio [OR]: 2.03 [95% CI: 1.04, 3.97]) and a 1 SD larger nMT-PRS (OR: 2.2 [95% CI: 1.68, 2.86]) were associated with elevated odds of dementia. Significant antagonistic interactions between the nMT-PRS and MT-hg K (OR: 0.45 [95% CI: 0.22, 0.9]) and MT-hg T (OR: 0.22 [95% CI: 0.1, 0.49]) were observed. Individual MT-hgs were not associated with AOO; however, a significant antagonistic interactions was observed between the nMT-PRS and MT-hg T (Hazard ratio: 0.62 [95% CI: 0.42, 0.91]) and a synergistic interaction between the nMT-PRS and MT-hg V (Hazard ratio: 2.28 [95% CI: 1.19, 4.35]). These results suggest that MT-hgs influence dementia risk and that variants in the nuclear and mitochondrial genome interact to influence the AOO of dementia.
KW - Alzheimer's disease
KW - Mitochondria
KW - Polygenic risk score
UR - http://www.scopus.com/inward/record.url?scp=85076229108&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076229108&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2019.09.007
DO - 10.1016/j.neurobiolaging.2019.09.007
M3 - Article
C2 - 31784277
AN - SCOPUS:85076229108
SN - 0197-4580
VL - 87
SP - 138.e7-138.e14
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -