gene-environment interaction; mitochondrial genes; polygenic score; Protein Serine-Threonine Kinases; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; LRRK2 protein, human; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics; Age of Onset; Risk Factors; Life Style; Mutation; Protein Serine-Threonine Kinases/genetics; Parkinson Disease/complications; Parkinson Disease; Neurology; Neurology (clinical)
Abstract :
[en] [en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lüth, Theresa ; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Gabbert, Carolin ; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Koch, Sebastian; Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, Kiel, Germany
König, Inke R; Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany
Caliebe, Amke; Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, Kiel, Germany
Laabs, Björn-Hergen; Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany
Hentati, Faycel; Neurology Department, National Institute of Neurology, Tunis, Tunisia
Sassi, Samia Ben; Neurology Department, National Institute of Neurology, Tunis, Tunisia
Amouri, Rim; Neurology Department, National Institute of Neurology, Tunis, Tunisia
Spielmann, Malte; Institute of Human Genetics, University of Lübeck, Lübeck, Germany
Klein, Christine; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
GRÜNEWALD, Anne ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology ; University of Lübeck > Institute of Neurogenetics
Farrer, Matthew J; Clinical Genomics, University of Florida, Gainesville, FL, USA
Trinh, Joanne; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Interaction of Mitochondrial Polygenic Score and Lifestyle Factors in LRRK2 p.Gly2019Ser Parkinsonism.
Publication date :
October 2023
Journal title :
Movement Disorders
ISSN :
0885-3185
eISSN :
1531-8257
Publisher :
John Wiley and Sons Inc, United States
Volume :
38
Issue :
10
Pages :
1837 - 1849
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Deutsche Forschungsgemeinschaft Michael J. Fox Foundation for Parkinson's Research
Funding text :
A special thanks to the families and patients who participated in this study. This project was supported by the DFG RU ProtectMove (DFG FOR2488), The Michael J. Fox Foundation (MJFF‐021227 and MJFF‐019271), and the Else Kröner‐Fresenius‐Stiftung. The Fox Insight Study (FI) is funded by The Michael J. Fox Foundation for Parkinson's Research. We would like to thank the Parkinson's community and 23andMe research participants and employees for making this research possible. Data used in the preparation of this manuscript were obtained from the Fox Insight database ( https://foxinsight-info.michaeljfox.org/insight/explore/insight.jsp ) on 18/10/2020. For up‐to‐date information on the study, visit https://foxinsight-info.michaeljfox.org/insight/explore/insight.jsp . Data used in the preparation of this article were obtained from the Accelerating Medicine Partnership® (AMP®) Parkinson's Disease (AMP PD) Knowledge Platform. For up‐to‐date information on the study, visit https://www.amp-pd.org . The AMP PD program is a public–private partnership managed by the Foundation for the National Institutes of Health and funded by the National Institute of Neurological Disorders and Stroke (NINDS) in partnership with the Aligning Science Across Parkinson's (ASAP) initiative; Celgene Corporation, a subsidiary of Bristol‐Myers Squibb Company; GlaxoSmithKline plc (GSK); The Michael J. Fox Foundation for Parkinson's Research; Pfizer Inc.; Sanofi US Services Inc.; and Verily Life Sciences. Accelerating Medicines Partnership and AMP are registered service marks of the U.S. Department of Health and Human Services. Clinical data and biosamples used in preparation of this article were obtained from (i) The Michael J. Fox Foundation for Parkinson's Research (MJFF) and National Institutes of Neurological Disorders and Stroke (NINDS) BioFIND study; (ii) Harvard Biomarkers Study (HBS); (iii) National Institute on Aging (NIA) International Lewy Body Dementia Genetics Consortium Genome Sequencing in Lewy Body Dementia Case–control Cohort (LBD); (iv) MJFF LRRK2 Cohort Consortium (LCC), (v) NINDS Parkinson's Disease Biomarkers Program (PDBP); (vi) MJFF Parkinson's Progression Markers Initiative (PPMI); and (vii) NINDS Study of Isradipine as a Disease‐modifying Agent in Subjects With Early Parkinson Disease, Phase 3 (STEADY‐PD3) and (viii) the NINDS Study of Urate Elevation in Parkinson's Disease, Phase 3 (SURE‐PD3). BioFIND is sponsored by The Michael J. Fox Foundation for Parkinson's Research (MJFF) with support from the National Institute for Neurological Disorders and Stroke (NINDS). The BioFIND investigators have not participated in reviewing the data analysis or content of the manuscript. For up‐to‐date information on the study visit michaeljfox.org/news/biofind . Genome sequence data for the Lewy body dementia case–control cohort were generated at the Intramural Research Program of the U.S. National Institutes of Health. The study was supported in part by the National Institute on Aging (Program #: 1ZIAAG000935) and the National Institute of Neurological Disorders and Stroke (Program #: 1ZIANS003154). The Harvard Biomarker Study (HBS) is a collaboration of HBS investigators (full list of HBS investigators at https://www.bwhparkinsoncenter.org/biobank/ ) and funded through philanthropy and NIH and non‐NIH funding sources. The HBS investigators have not participated in reviewing the data analysis or content of the manuscript. PPMI is sponsored by The Michael J. Fox Foundation for Parkinson's Research and supported by a consortium of scientific partners (full list of all the PPMI funding partners at https://www.ppmi-info.org/about-ppmi/who-we-are/study-sponsors ). The PPMI investigators have not participated in reviewing the data analysis or content of the manuscript. For up‐to‐date information on the study visit www.ppmi-info.org . The Parkinson's Disease Biomarker Program (PDBP) consortium is supported by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. A full list of PDBP investigators can be found at https://pdbp.ninds.nih.gov/policy . The PDBP investigators have not participated in reviewing the data analysis or content of the manuscript. The Study of Isradipine as a Disease‐modifying Agent in Subjects With Early Parkinson Disease, Phase 3 (STEADY‐PD3) is funded by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health with support from The Michael J. Fox Foundation and the Parkinson Study Group. For additional study information, visit https://clinicaltrials.gov/ct2/show/study/NCT02168842 . The STEADY‐PD3 investigators have not participated in reviewing the data analysis or content of the manuscript. The Study of Urate Elevation in Parkinson's Disease, Phase 3 (SURE‐PD3) is funded by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health with support from The Michael J. Fox Foundation and the Parkinson Study Group. For additional study information visit https://clinicaltrials.gov/ct2/show/NCT02642393 . The SURE‐PD3 investigators have not participated in reviewing the data analysis or content of the manuscript. Open Access funding enabled and organized by Projekt DEAL.: This project was supported by the DFG RU ProtectMove (DFG FOR2488), The Michael J. Fox Foundation (MJFF‐021227 and MJFF‐019271), and the Else Kröner‐Fresenius‐Stiftung. Funding agenciesA special thanks to the families and patients who participated in this study. This project was supported by the DFG RU ProtectMove (DFG FOR2488), The Michael J. Fox Foundation (MJFF-021227 and MJFF-019271), and the Else Kröner-Fresenius-Stiftung. The Fox Insight Study (FI) is funded by The Michael J. Fox Foundation for Parkinson's Research. We would like to thank the Parkinson's community and 23andMe research participants and employees for making this research possible. Data used in the preparation of this manuscript were obtained from the Fox Insight database (https://foxinsight-info.michaeljfox.org/insight/explore/insight.jsp) on 18/10/2020. For up-to-date information on the study, visit https://foxinsight-info.michaeljfox.org/insight/explore/insight.jsp. Data used in the preparation of this article were obtained from the Accelerating Medicine Partnership® (AMP®) Parkinson's Disease (AMP PD) Knowledge Platform. For up-to-date information on the study, visit https://www.amp-pd.org. The AMP PD program is a public–private partnership managed by the Foundation for the National Institutes of Health and funded by the National Institute of Neurological Disorders and Stroke (NINDS) in partnership with the Aligning Science Across Parkinson's (ASAP) initiative; Celgene Corporation, a subsidiary of Bristol-Myers Squibb Company; GlaxoSmithKline plc (GSK); The Michael J. Fox Foundation for Parkinson's Research; Pfizer Inc.; Sanofi US Services Inc.; and Verily Life Sciences. Accelerating Medicines Partnership and AMP are registered service marks of the U.S. Department of Health and Human Services. Clinical data and biosamples used in preparation of this article were obtained from (i) The Michael J. Fox Foundation for Parkinson's Research (MJFF) and National Institutes of Neurological Disorders and Stroke (NINDS) BioFIND study; (ii) Harvard Biomarkers Study (HBS); (iii) National Institute on Aging (NIA) International Lewy Body Dementia Genetics Consortium Genome Sequencing in Lewy Body Dementia Case–control Cohort (LBD); (iv) MJFF LRRK2 Cohort Consortium (LCC), (v) NINDS Parkinson's Disease Biomarkers Program (PDBP); (vi) MJFF Parkinson's Progression Markers Initiative (PPMI); and (vii) NINDS Study of Isradipine as a Disease-modifying Agent in Subjects With Early Parkinson Disease, Phase 3 (STEADY-PD3) and (viii) the NINDS Study of Urate Elevation in Parkinson's Disease, Phase 3 (SURE-PD3). BioFIND is sponsored by The Michael J. Fox Foundation for Parkinson's Research (MJFF) with support from the National Institute for Neurological Disorders and Stroke (NINDS). The BioFIND investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to-date information on the study visit michaeljfox.org/news/biofind. Genome sequence data for the Lewy body dementia case–control cohort were generated at the Intramural Research Program of the U.S. National Institutes of Health. The study was supported in part by the National Institute on Aging (Program #: 1ZIAAG000935) and the National Institute of Neurological Disorders and Stroke (Program #: 1ZIANS003154). The Harvard Biomarker Study (HBS) is a collaboration of HBS investigators (full list of HBS investigators at https://www.bwhparkinsoncenter.org/biobank/) and funded through philanthropy and NIH and non-NIH funding sources. The HBS investigators have not participated in reviewing the data analysis or content of the manuscript. PPMI is sponsored by The Michael J. Fox Foundation for Parkinson's Research and supported by a consortium of scientific partners (full list of all the PPMI funding partners at https://www.ppmi-info.org/about-ppmi/who-we-are/study-sponsors). The PPMI investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to-date information on the study visit www.ppmi-info.org. The Parkinson's Disease Biomarker Program (PDBP) consortium is supported by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. A full list of PDBP investigators can be found at https://pdbp.ninds.nih.gov/policy. The PDBP investigators have not participated in reviewing the data analysis or content of the manuscript. The Study of Isradipine as a Disease-modifying Agent in Subjects With Early Parkinson Disease, Phase 3 (STEADY-PD3) is funded by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health with support from The Michael J. Fox Foundation and the Parkinson Study Group. For additional study information, visit https://clinicaltrials.gov/ct2/show/study/NCT02168842. The STEADY-PD3 investigators have not participated in reviewing the data analysis or content of the manuscript. The Study of Urate Elevation in Parkinson's Disease, Phase 3 (SURE-PD3) is funded by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health with support from The Michael J. Fox Foundation and the Parkinson Study Group. For additional study information visit https://clinicaltrials.gov/ct2/show/NCT02642393. The SURE-PD3 investigators have not participated in reviewing the data analysis or content of the manuscript. Open Access funding enabled and organized by Projekt DEAL.
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