Mitonuclear interactions influence Alzheimer's disease risk

Shea J Andrews; Brian Fulton-Howard; Christopher Patterson; G Peggy McFall; Alden Gross; Elias K Michaelis; Alison Goate; Russell H Swerdlow; Judy Pa; Alzheimer's Disease Neuroimaging Initiative

doi:10.1016/j.neurobiolaging.2019.09.007

Mitonuclear interactions influence Alzheimer's disease risk

Neurobiol Aging. 2020 Mar:87:138.e7-138.e14. doi: 10.1016/j.neurobiolaging.2019.09.007. Epub 2019 Sep 24.

Authors

Shea J Andrews¹, Brian Fulton-Howard¹, Christopher Patterson², G Peggy McFall³, Alden Gross⁴, Elias K Michaelis⁵, Alison Goate¹, Russell H Swerdlow⁶, Judy Pa⁷; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Neurology, Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Department of Psychology, University of Alberta, Edmonton, Canada; Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada.
⁴ Department of Epidemiology, JHSPH Center on Aging and Health, Baltimore, MD, USA.
⁵ Higuchi Biosciences Center and Alzheimer's Disease Center, University of Kansas, Lawrence, KS, USA.
⁶ Department of Neurology, Alzheimer's Disease Center, University of Kansas Medical Center, Fairway, KS, USA.
⁷ Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Neurology, Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: jpa@ini.usc.edu.

PMID: 31784277
PMCID: PMC7205324
DOI: 10.1016/j.neurobiolaging.2019.09.007

Abstract

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.

Keywords: Alzheimer's disease; Mitochondria; Polygenic risk score.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / genetics*
DNA, Mitochondrial / genetics*
Epistasis, Genetic
Female
Genetic Association Studies*
Genome, Human / genetics
Haplotypes
Humans
Male
Multifactorial Inheritance
Polymorphism, Single Nucleotide
Risk

Substances

DNA, Mitochondrial

Abstract

Publication types

MeSH terms

Substances

Grants and funding