Interaction of Mitochondrial Polygenic Score and Lifestyle Factors in LRRK2 p.Gly2019Ser Parkinsonism

Theresa Lüth; Carolin Gabbert; Sebastian Koch; Inke R König; Amke Caliebe; Björn-Hergen Laabs; Faycel Hentati; Samia Ben Sassi; Rim Amouri; Malte Spielmann; Christine Klein; Anne Grünewald; Matthew J Farrer; Joanne Trinh

doi:10.1002/mds.29563

Interaction of Mitochondrial Polygenic Score and Lifestyle Factors in LRRK2 p.Gly2019Ser Parkinsonism

Mov Disord. 2023 Oct;38(10):1837-1849. doi: 10.1002/mds.29563. Epub 2023 Jul 21.

Authors

Affiliations

¹ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
² Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, Kiel, Germany.
³ Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.
⁴ Neurology Department, National Institute of Neurology, Tunis, Tunisia.
⁵ Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
⁶ Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
⁷ Clinical Genomics, University of Florida, Gainesville, FL, USA.

PMID: 37482924
DOI: 10.1002/mds.29563

Abstract

Background: A mitochondrial polygenic score (MGS) is composed of genes related to mitochondrial function and found to be associated with Parkinson's disease (PD) risk.

Objective: To investigate the impact of the MGS and lifestyle/environment on age at onset (AAO) in LRRK2 p.Gly2019Ser parkinsonism (LRRK2-PD) and idiopathic PD (iPD).

Methods: We included N = 486 patients with LRRK2-PD and N = 9259 with iPD from the Accelerating Medicines Partnership® Parkinson's Disease Knowledge Platform (AMP-PD), Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data were used to perform the MGS analysis. Additionally, lifestyle/environmental data were obtained from the PD Risk Factor Questionnaire (PD-RFQ). Linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO.

Results: Our derived MGS was significantly higher in PD cases compared with controls (P = 1.1 × 10^-8 ). We observed that higher MGS was significantly associated with earlier AAO in LRRK2-PD (P = 0.047, β = -1.40) and there was the same trend with a smaller effect size in iPD (P = 0.231, β = 0.22). There was a correlation between MGS and AAO in LRRK2-PD patients of European descent (P = 0.049, r = -0.12) that was visibly less pronounced in Tunisians (P = 0.449, r = -0.05). We found that the MGS interacted with caffeinated soda consumption (P = 0.003, β = -5.65) in LRRK2-PD and with tobacco use (P = 0.010, β = 1.32) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeinated soda or were non-smokers.

Conclusions: The MGS was more strongly associated with earlier AAO in LRRK2-PD compared with iPD. Caffeinated soda consumption or tobacco use interacted with MGS to predict AAO. Our study suggests gene-environment interactions as modifiers of AAO in LRRK2-PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: gene-environment interaction; mitochondrial genes; polygenic score.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Age of Onset
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
Life Style
Mutation
Parkinson Disease* / complications
Protein Serine-Threonine Kinases* / genetics
Risk Factors

Substances

Protein Serine-Threonine Kinases
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
LRRK2 protein, human

Grants and funding

U24 NS095871/NS/NINDS NIH HHS/United States