Commentary: Pesticides and GBA1 pathogenic variants in Parkinson's disease: An emerging and potentially dangerous association

Abstract

We comment here on the recently published paper by Ostentag et al., 2026, which examined self-reported environmental exposures in a group of patients with Parkinson's Disease (PD). Patients with GBA1-associated Parkinson's Disease (PD) were two times more likely to have been exposed to occupational pesticides compared to those with idiopathic PD, while there was no difference for any other exposure between the two groups. Combined with previous work, these findings suggest that GBA1 pathogenic variant status in combination with exposure to pesticides leads to a high risk of developing PD, and have several implications: at the genetic epidemiological level, they provide a partial explanation for the missing penetrance of GBA1 pathogenic variants; at the biological level, they suggest that the biological mechanisms of pathogenicity conferred by the genetic predisposition and the environmental exposure may converge on the same pathways, potentially involving the interplay between lysosomal and mitochondrial function; at the public health level, they suggest that exposure to even low levels of environmental toxins may be especially deleterious for genetically susceptible individuals with GBA1 pathogenic variants. Further studies are needed to verify these results using rigorous methods for exposure ascertainment, to identify the exact class of substances underlying this association and their biological mechanisms in this context, and to determine the exposure levels that could be considered safe in this vulnerable population.

There is a wealth of evidence indicating that specific environmental and genetic factors increase Parkinson's Disease (PD) risk, yet the interaction between genetic susceptibility and exposure to potential toxicants is relatively understudied. As an example of such an approach, indices of air pollution appear to act synergistically with the PD Polygenic Risk Score (PRS) to increase PD risk.^1,2 Pesticide exposure, especially occupational, has long been considered an environmental risk factor for PD, and genetic variations in genes that are involved in metabolic pathways related to these toxicants may modulate this risk. ³ Yet relatively little is known about the interaction of pesticide exposure with pathogenic variants in GBA1 and LRRK2, the commonest genetic underpinnings of PD worldwide. Ostentag et al. (2026) ⁴ provide evidence in a moderately sized, well-characterized Parkinson's Disease (PD) cohort in Turkey that self-reported occupational exposure to pesticides is approximately twice as frequent in PD patients with GBA1 pathogenic variants (GBA-PD) than in PD without such variants. This finding broadly confirms three previous reports, which showed even higher odds ratios when comparing GBA-PD either to idiopathic PD (iPD) ⁵ or to control subjects without PD carrying GBA1 pathogenic variants.^6,7 It should be noted, however, that one very large study in the 23andMe, Inc. research dataset did not find such an association. Caveats in that study include restriction to common and less severe GBA1 variants and the examination of only residential exposure, which was quite high in both GBA-PD and control groups. ⁸ The study of Ostentag et al. (2026) ⁴ did not find evidence that pesticide exposure led to a higher disease severity in GBA-PD, or that it hastened the age of disease onset; similarly, Brown et al. (2024), ⁶ in the PPMI cohort, detected no significant effect of pesticide exposure on PD progression in the GBA-PD group.

Taken together, these studies across diverse ethnic backgrounds and geographic regions support the hypothesis that pesticide exposure may be associated with the development, but not with the severity or progression of PD, in carriers of GBA1 pathogenic variants, and that this risk is greater than that conferred to individuals without such variants. In other words, pesticide exposure appears more strongly linked to whether PD develops than to its severity or progression in genetically susceptible individuals. These observations carry several implications.

Given the 10–20% penetrance of GBA1 pathogenic variants for PD development, ⁹ there has been an intense search to identify additional factors leading to GBA-PD. The gene–environment studies mentioned above suggest that among environmental factors traditionally linked to iPD, pesticide exposure may be particularly relevant in modulating penetrance in GBA1 carriers, as it was the only factor studied that showed an association. If the high odds ratios (of 5,4 to 8,4) for pesticide exposure reported when comparing GBA-PD to non-manifesting GBA mutation carriers^6,7 hold up in larger studies with systematically assessed exposure data, this could account for a significant proportion of the “lost” penetrance. However, this interpretation remains provisional and will require larger population-level prospective epidemiological studies that assess penetrance and use relevant detailed exposure data and control for possible confounders.

Naturally, genetic modifiers may also account for “lost” penetrance. One strategy is to assess known genetic factors that increase iPD risk, as summarized by the PRS, in GBA1 carriers. Such analyses suggest that PRS confers a similar magnitude of risk for iPD and GBA-PD, ¹⁰ implying that, at first glance, there may be no major interaction between GBA mutation status and a specific genetic factor known to be linked to iPD. In this vein, it is interesting to note that in Simitsi et al. (2018) ⁵ and in the present Ostentag et al. (2026) ⁴ study, pesticide exposure is reported at significantly higher levels in GBA-PD compared to iPD, suggesting that there is a synergistic, and not just additive, “dual-hit” effect.

At the biological level, how could this interaction work? Pesticides are traditionally linked to mitochondrial dysfunction, while GBA1 is a known lysosomal gene, leading, amongst other pieces of data, to the more general idea that dysfunction of the Autophagy Lysosome pathway (ALP) is a significant factor in PD pathogenesis. Importantly, there is evidence that mitochondrial dysfunction may be secondarily mediated by GBA1 variants through inhibition of autophagy and mitophagy, ¹¹ while GBA1 variants may also disrupt lysosomal-mitochondrial contacts, leading to secondary mitochondrial abnormalities. ¹² On the other hand, pesticides may affect not only mitochondrial, but also autophagy pathways. ¹³ Potentially, therefore, synergistic effects between pesticides and genetic alterations at the ALP could explain these recent gene-environment findings in the context of GBA-PD. Consistent with this, defects in various genes linked to autophagy appear to confer an increased risk of severe PD, specifically among individuals exposed to high levels of “cotton cluster” pesticides, in a California cohort. ¹⁴ Furthermore, beyond cell-autonomous neuronal effects, immune system-mediated inflammatory pathways, which are affected both by GBA variant status and pesticide exposure, may provide the basis for relevant biological interactions. ¹⁵ Gene-environment interactions are also important to consider in the context of heat map studies that report the incidence of PD across various geographical regions, such as the recently published work from the Netherlands. ¹⁶ Although the geographical location of the inhabitants serves as a general proxy for ambiental exposures, studies such as the one commented upon here suggest that the genetic susceptibility of individuals, which may be different across distinct geographical areas, should also be taken into account.

Beyond the above biological and epidemiological considerations, it has become apparent that PD should be treated as a public health problem with real opportunities for prevention. The World Health Organization (WHO) has identified environmental toxicants as modifiable risk factors to PD, calling for reduced exposure as part of a comprehensive prevention strategy. ¹⁷ Recent reviews show that the epidemiological and experimental evidence linking specific pesticides to PD risk is consistent, biologically plausible, and strong enough to support action, despite some methodological limitations. ¹⁸ In this context, Ostentag et al. (2026) ⁴ and the other gene/environment studies mentioned above indicate that genetic susceptibility may lower the threshold at which environmental exposures become pathogenic, suggesting that exposure reduction may be especially relevant in such genetically susceptible individuals.

These findings carry important implications for public health policy. A recent opinion paper pointed out that regulatory systems often assume equal susceptibility across populations. They also tend to require proof of harm rather than safety and rarely consider long latency periods or gene–environment interactions. ¹⁹ Uniform exposure limits may inadequately protect population subgroups, including individuals with lysosomal or mitochondrial susceptibility, such as carriers of GBA1 pathogenic variants. While incorporation of genetic information into regulation raises ethical and practical challenges, the literature converges on the need for population-level exposure reduction, such as stricter regulation of known neurotoxicants, improved environmental monitoring and better enforcement of protective measures in agricultural and industrial settings.^17–19 These approaches align with the precautionary principle and underscore prevention as a credible long-term strategy to curb the rising global burden of PD.

While GBA1 variants alone confer incomplete penetrance, pesticide exposure remains frequent in agricultural, rural, and lower-income settings, where regulatory oversight and protective measures are often variable. Even a modest increase in disease risk or penetrance among genetically susceptible individuals could translate into a population-level impact, given the scale and chronicity of exposure and the common presence of such pathogenic variants, especially in particular ethnic groups. This framing shifts the relevance of GBA1–environment interactions beyond individual risk prediction toward actionable prevention, highlighting exposure reduction as a lever to mitigate disease burden. In this sense, gene–environment findings should not argue for genetically targeted regulation but rather reinforce the urgency of broad health policies that reduce neurotoxic exposures for all, while potentially conferring more benefit to biologically vulnerable subgroups. The work by Ostentag et al. (2026) ⁴ adds to a growing body of converging evidence suggesting that gene–environment interactions are not peripheral, but central, to understanding and potentially preventing PD.