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bioRxiv · 10.1101/2020.11.06.371286

Mitochondrial pathway polygenic risk scores are associated with Alzheimer's Disease

Paliwal, D.·McInerney, T. W.·Pa, J.·Swerdlow, R. H.·Easteal, S.·Andrews, S. J.
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Abstract

INTRODUCTIONGenetic, animal and epidemiological studies involving biomolecular and clinical endophenotypes implicate mitochondrial dysfunction in Alzheimers disease (AD) pathogenesis. Polygenic risk scores (PRS) provide a novel approach to assess biological pathway-associated disease risk by combining the effects of variation at multiple, functionally related genes. METHODSWe investigated associations of PRS for genes involved in 12 mitochondrial pathways (pathway-PRS) related to AD in 854 participants from Alzheimers Disease Neuroimaging Initiative. RESULTSPathway-PRS for four mitochondrial pathways are significantly associated with increased AD risk: (i) response to oxidative stress (OR: 2.01 [95% Cl: 1.71, 2.37]); (ii) mitochondrial transport (OR: 1.81 [95% Cl: 1.55, 2.13]); (iii) hallmark oxidative phosphorylation (OR: 1.23 [95% Cl: 1.07, 1.41]); and (iv) mitochondrial membrane potential regulation (OR: 1.18 [95% Cl: 1.03, 1.36]). DISCUSSIONTherapeutic approaches targeting these pathways may have potential for modifying AD pathogenesis. Further investigation is required to establish a causal role for these pathways in AD pathology.

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Paliwal, D., McInerney, T. W., Pa, J., Swerdlow, R. H., Easteal, S., Andrews, S. J.. 2020-11-06. Mitochondrial pathway polygenic risk scores are associated with Alzheimer's Disease. https://doi.org/10.1101/2020.11.06.371286

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