Mitochondrial insertions/deletions (INDELs) burden in Parkinson's disease: an analysis from a Brazilian cohort

Mitochondrial DNA (mtDNA) alterations are increasingly associated with Parkinson's disease (PD), particularly due to their role in oxidative stress. However, the contribution of mtDNA insertions and deletions (INDELs) to PD remains poorly understood, particularly in genetically admixed populations such as Brazilians.

To explore this, we sequenced the complete mtDNA from blood samples of 179 admixed individuals from the Brazilian Amazon (104 people with PD and 75 controls). Data processing included FastQC, MultiQC, FastP, BWA, and mtDNA-Server 2.

We identified a significantly higher burden of mtDNA INDELs in PD compared with controls in Complex I genes (OR = 9.23; 95% CI: 2.22-63.55; FDR = 0.044). Differences in heteroplasmy levels were also observed in the ATP6, ND4, and ND5 genes. Importantly, we discovered seven new PD-associated INDELs (m.13763_13763delinsCCA, m.13885_13885delinsCTG, m.13888_13890delinsT, m.13767_13769delinsC, m.13810_13812delinsG, m.13813_13813delinsGCA, and m.13764_13764delinsCAT) that are particularly more frequent among individuals harboring uniparental lineages of Native American origin.

Our findings report novel mtDNA INDELs, particularly in Complex I, which may contribute to PD susceptibility and highlight the importance of investigating mitochondrial genomic variation in underrepresented populations. These associations should be interpreted as preliminary, and further longitudinal studies with independent cohorts are required to confirm these observations.