Objective: To present the first genetic findings of the MEX-PD cohort, with a specific focus on analyzing the role of MTHFR variants

Background: Despite significant efforts, the genetic risk factors for Parkinson’s disease (PD) in Mexico remain poorly understood. The Mexican Parkinson’s Research Network (MEX-PD), established in 2021, helps to address this gap employing a whole-genome genotyping approach to explore PD’s genetic basis in the Mexican population. As an example of the potential of MEX-PD, here we explore the case of the gene MTHFR, variation in which has been associated with an increased PD risk in European populations.

Method: Participants with PD and controls were recruited from medical centers and public spaces across Mexico. Informed consent was obtained, and the study received ethical approval from the UNAM INB Research Ethics Committee. Participants provided DNA samples via buccal swabs. After DNA extraction, samples underwent genotyping with the Illumina NeuroBooster Array, variant calling, rigorous quality control and imputation using the TOPMed Imputation server. A set of selected genetic variants were analyzed for frequency and association to PD risk and later cross-checked in the Latin-American (AMR), African (AFR) and European (EUR) ancestry cohorts from the Global Parkinson’s Genetics Program (GP2) release 7, however only variants in MTHFR are shown here.  Furthermore, coding variants in MTHFR were analyzed using RVTests, applying SKAT and SKAT-O burden tests.

Results: Following quality control, genetic data from 294 samples were analyzed. The generalized linear model regression adjusted by age, sex and the first five principal components analyses identified the missense variant  rs1801133 in MTHFR, as nominally significant in our MEX-PD cohort, replicating a previous finding in Mexican people, but not in the AFR, AMR, or EUR cohorts of GP2 (Figure 1), warranting further investigation. However, burden analysis of coding variants in MTHFR did not reveal any significant findings.

Conclusion:

The genetic analysis by MEX-PD advances understanding of the genetic landscape of PD in the Mexican population. The present showed a nominal association of the MTHFR rs1801133 variant with PD in the Mexican cohort, but no significant results were found in other ancestry cohorts or burden analysis, highlighting the importance of further genetic studies on MTHFR in diverse populations.

Fig 1

References: Bandres-Ciga, S. et al. (2023). medRxiv,
Danecek, P. et al. (2021). Gigascience, 10,
Chang, C.C. et al. (2015). Gigascience, 4, 7
Manichaikul, A. et al. (2010). Bioinformatics, 26, 2867–2873
Leal, T.P. et al. (2022). Comput. Struct. Biotechnol. J., 20, 1821–1828
Taliun, D. et al. (2021). Nature, 590, 290–299
Das, S. et al. (2016). Nat. Genet., 48, 1284–1287
Fuchsberger, C. et al. (2015). Bioinformatics, 31, 782–784
Byrska-Bishop, M. et al. (2022). Cell, 185, 3426–3440.e19
Shriner, D. et al. (2023). HGG Adv, 4, 100235
Markopoulou, K. et al. (2021). Front. Neurol., 12, 662278
Romero-Gutiérrez, E. et al. (2021). NPJ Parkinsons Dis, 7, 13
Saffie-Awad, P. et al. (2024). medRxiv, 2023.11.28.23299090
Loesch, D.P. et al. (2021). Ann. Neurol., 90, 353–365

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MDS Abstracts - https://www.mdsabstracts.org/abstract/first-insights-into-genetic-findings-from-the-mexican-parkinsons-research-network-mex-pd-the-case-of-mthfr/