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. 2023 Jan 5;146(1):42-49.
doi: 10.1093/brain/awac327.

Mitochondrial haplogroups and cognitive progression in Parkinson's disease

Ganqiang Liu  1 , Chunming Ni  1 , Jiamin Zhan  1 , Weimin Li  1 , Junfeng Luo  1 , Zhixiang Liao  2   3 , Joseph J Locascio  2   3   4 , Wenbiao Xian  5 , Ling Chen  5 , Zhong Pei  5 , Jean-Christophe Corvol  6 , Jodi Maple-Grødem  7   8 , Meghan C Campbell  9 , Alexis Elbaz  10 , Suzanne Lesage  6 , Alexis Brice  6 , Albert Y Hung  4 , Michael A Schwarzschild  4 , Michael T Hayes  11 , Anne-Marie Wills  4 , Bernard Ravina  12 , Ira Shoulson  13 , Pille Taba  14   15 , Sulev Kõks  16   17 , Thomas G Beach  18 , Florence Cormier-Dequaire  6 , Guido Alves  7   8   19 , Ole-Bjørn Tysnes  20   21 , Joel S Perlmutter  9   22   23 , Peter Heutink  24 , Jacobus J van Hilten  25 , Roger A Barker  26   27 , Caroline H Williams-Gray  26 , Clemens R Scherzer  2   3   4   11 ; International Genetics of Parkinson Disease Progression (IGPP) Consortium
Collaborators, Affiliations

Mitochondrial haplogroups and cognitive progression in Parkinson's disease

Ganqiang Liu et al. Brain. .

Abstract

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

Keywords: Parkinson’s disease; cognitive progression; mitochondrial haplogroups.

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Conflict of interest statement

Outside this work, C.R.S. has served as consultant, scientific collaborator or on scientific advisory boards for Sanofi, Berg Health, Pfizer and Biogen and has received grants from NIH, U.S. Department of Defense, American Parkinson Disease Association, and the Michael J Fox Foundation (MJFF). C.R.S. is named as co-inventor on U.S. patent applications held by Brigham and Women’s Hospital relating to therapeutics; biomarkers; and polygenic scores for neurodegenerative diseases. M.A.S. has no conflict of interest related to this work. Outside this work, M.A.S. has received grants from NINDS, DoD, MJFF, the Parkinson’s Foundation and Farmer Family Foundation and has served as a consultant to commercial programs: Eli Lilly & Co (data monitoring committee), Prevail Therapeutics (scientific advisory board) and Denali Therapeutics (scientific advisory board); and via the Parkinson Study Group to nQ Medical (scientific advisory board), Chase Therapeutics (scientific advisory board) and Partner Therapeutics (scientific advisory board). A.-M.W. has received research funding from the ALS Association, the Parkinson's Foundation, has participated in clinical trials funded by Acorda, Biogen, Bristol-Myers Squibb, Sanofi/Genzyme, Pfizer and Abbvie and received consultant payments from Mitsubishi Tanabe and Accordant. J.-C.C. has no conflict of interest related to this work. Outside this work, J.C.C. has received honoraria for consulting in advisory boards for Abbvie, Actelion, Air Liquide, Biogen, BMS, BrainEver, Clevexel, Denali, Pfizer, Theranexus and Zambon. B.R. is an employee of and holds equity in Praxis Precision Medicines and is an advisor for Caraway Therapeutics and Brain Neurotherapy Bio. I.S. is the Principal Investigator of a MJFF Computational Science Grant (2017–19). S.K. is supported by Multiple Sclerosis of Western-Australia (MSWA) and the Perron Institute. P.H. is a Scientific Advisor of Neuron23. T.G.B has no conflict of interest related to this work. Outside this work, T.G.B. has received grants from NIA, NINDS, MJFF and the State of Arizona, has served as a scientific advisory board member (with stock options) and consultant to Vivid Genomics, Inc. and has received honoraria from the World PD Coalition. J.J.v.H. has no conflict of interest related to this work. Outside this work, J.J.v.H. has received grants from the Alkemade-Keuls Foundation, Stichting Parkinson Fonds, Parkinson Vereniging, The Netherlands Organisation for Health Research and Development, The Netherlands Organisation for Scientific Research, Hersenstichting, AbbVie, MJFF and research support from Hoffmann-La-Roche, Lundbeck and the Centre of Human Drug Research. R.A.B. has no conflict of interest related to this work. Outside this work, R.A.B. received consultancy monies from LCT, FCDI, Novo Nordisk, Cellino, Sana, UCB; received royalties from Wiley and Springer-Nature; grant funding from CPT, NIHR Cambridge Biomedical Research Centre (146281), MRC, Wellcome (203151/Z/16/Z) and Rosetrees Trust (A1519 M654). C.H.W.-G. has no conflict of interest related to this work. C.H.W.-G. is supported by a RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1) and the NIHR Cambridge Biomedical Research Centre and received grant support from MJFF, the Evelyn Trust, the Cure Parkinson’s Trust, Parkinson’s UK, the Rosetrees Trust and the Cambridge Centre for Parkinson-Plus. C.H.W.-G. has received honoraria from Lundbeck and Profile Pharma Ltd and consultancy payments from Modus Outcomes and Evidera. The other authors report no competing interests.

Figures

Figure 1
Figure 1
Mitochondrial haplogroups and risk for GCI over time in patients with PD. The forest plot shows HRs for global cognitive impairment in specific types of macro-haplogroups compared to macro-haplogroup H in patients with PD from the discovery (A), replication (B) and combined (C) populations. The squares represent point estimates, with the sides of the square inversely proportional to the standard error of the estimates. The horizontal lines indicate 95% CIs of the estimates. (D) Covariate-adjusted survival curves for patients with PD in macro-haplogroups J, T and U# (cyan line) and those in macro-haplogroups H (magenta line).
Figure 2
Figure 2
mtSNPs associated with cognitive progression in patients with PD. (A) Association plot of SNPs in mtDNA associated with risk of developing global cognitive impairment (dot) in the combined population. The outside labels indicate mitochondrial genes; circular axis from outside to inside represents the value of -log10(P) from 0 to 5; SNPs with P < 0.05 are shown in magenta, while SNPs with P ≥ 0.05 are shown in grey. (B) Covariate-adjusted survival curves for patients with PD carrying mtDNA m.2706G (cyan line) and those with m.2706A (magenta line). m.2706A was used as the reference allele to calculate the HR from the Cox PH analysis; P values from two-sided Wald tests. (C) Overlap between carriers of the m.2706A>G and the m.14766C>T variant. Out of 2611 m.2706G allele carriers and 2347 m.14766T allele carriers, 2342 individuals carried both alleles. Out of 1830 m.2706A allele carriers and 2080 m.14766C allele carriers, 1819 individuals carried both alleles.
Figure 3
Figure 3
Effects of GBA variants and mtSNPs on global cognitive impairment in patients with PD. Covariate-adjusted survival curves for patients with PD stratified into four subgroups: GBA-negative and non-m.2706A carriers (n = 1257), GBA-negative and m.2706A carriers (n = 891), GBA-positive and non-m.2706G carriers (n = 132) and GBA-positive and m.2706A carriers (n = 96). HR and P-values were calculated adjusting for clinical covariates and study cohort as a random term. The group of GBA-negative and non-m.2706A carriers is denoted as reference group (REF) in this Cox PH analysis.
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