Objective: To investigate the relationship between COMT genetic variants and PD risk across diverse ancestries.

Background: The enzyme catechol-O-methyltransferase (COMT; OMIM:116790) plays a crucial role in catecholamine metabolism in the brain. While numerous studies have explored associations between COMT variants and PD susceptibility [1], particularly the Val158Met (rs4680), and their impact on levodopa-induced dyskinesia (LID) [2,3], cognitive decline [4–6], and motor fluctuations [7], findings remain inconsistent, leaving the role of COMT and variants in close proximity unresolved.

Method: We analyzed COMT variants in 2,251 PD patients and 2,835 controls of European descent using whole-genome sequencing from the Accelerating Medicines Partnership-Parkinson Disease (AMP-PD; https://amp-pd.org/), along with 20,427 PD patients and 11,837 controls from 10 ancestries using genotyping data from the Global Parkinson’s Genetics Program (GP2; https://gp2.org/es/). SNP-phenotype association analyses were performed with a generalized linear model in PLINK 2.0. Gene-based burden analysis was performed to assess the cumulative effects of specific COMT variant sets on PD risk using RVTESTS. Furthermore, we examined clinical data of individuals of European ancestry in GP2 and AMP-PD to explore the impact of COMT variants on cognitive and motor function, as well as LID development.

Results: Utilizing the largest case-control datasets to date, no significant enrichment of COMT risk alleles in PD patients was observed across any ancestry group. Specifically, the variants p.Val158Met (rs4680) and p.His62= (rs4633) were nominally significantly associated with PD risk in Central Asian and European ancestry groups, the variant c.-98A>G (rs6269) in Europeans, c.*764C>T (rs165728) in Ashkenazi Jewish and Middle Eastern, and p.Ala72Ser (rs6267) in East Asians. However, these associations did not remain significant after multiple testing corrections. The cumulative effect of coding or potentially functional variants did not show a significant association with PD risk. Among Europeans, no correlations with cognitive decline, motor function, motor complications, or time to LID onset were observed.

Conclusion: Our results show no association between COMT and PD risk that passes multiple test correction, emphasizing the need for larger, diverse cohorts to confirm its role in PD development and progression.

References: 1. Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG. COMT gene and risk for Parkinson’s disease: a systematic review and meta-analysis. Pharmacogenet Genomics. 2014;24:331–9.
2. Dwivedi A, Dwivedi N, Kumar A, Singh VK, Pathak A, Chaurasia RN, et al. Association of Catechol-O-Methyltransferase Gene rs4680 Polymorphism and Levodopa Induced Dyskinesia in Parkinson’s Disease: A Meta-Analysis and Systematic Review. J Geriatr Psychiatry Neurol. 2023;36:98–106.
3. Yin Y, Liu Y, Xu M, Zhang X, Li C. Association of COMT rs4680 and MAO-B rs1799836 polymorphisms with levodopa-induced dyskinesia in Parkinson’s disease-a meta-analysis. Neurol Sci. 2021;42:4085–94.
4. Barnett JH, Scoriels L, Munafò MR. Meta-analysis of the cognitive effects of the catechol-O-methyltransferase gene Val158/108Met polymorphism. Biol Psychiatry. 2008;64:137–44.
5. Lin C-H, Fan J-Y, Lin H-I, Chang C-W, Wu Y-R. Catechol-O-methyltransferase (COMT) genetic variants are associated with cognitive decline in patients with Parkinson’s disease. Parkinsonism Relat Disord. 2018;50:48–53.
6. Tang C, Wang W, Shi M, Zhang N, Zhou X, Li X, et al. Meta-Analysis of the Effects of the Catechol-O-Methyltransferase Val158/108Met Polymorphism on Parkinson’s Disease Susceptibility and Cognitive Dysfunction. Front Genet. 2019;10:454351.
7. Soraya GV, Ulhaq ZS, Shodry S, A’raaf Sirojan Kusuma M, Herawangsa S, Sativa MO, et al. Polymorphisms of the dopamine metabolic and signaling pathways are associated with susceptibility to motor levodopa-induced complications (MLIC) in Parkinson’s disease: a systematic review and meta-analysis. Neurol Sci. 2022;43:3649–70.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/does-comt-play-a-role-in-parkinsons-disease-susceptibility-across-diverse-ancestral-populations/