Exploring environmental modifiers of LRRK2-associated Parkinson’s disease penetrance: An exposomics and metagenomics pilot study on household dust

[Display omitted] •Exposomics of household dust revealed several significant chemicals of interest.•Chemical replacements Bisphenol S (BPS) and PFBuS may modify LRRK2 penetrance.•BPS negatively impacted mitochondria in dopaminergic neuron-enriched cultures.•Benzothiazoles may be degraded by Pseudomonas spp. identified by metagenomics.•Lipid species were altered in the serum of the PD+/LRRK2+ individuals vs controls. Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are a primary monogenic cause of Parkinson’s disease (PD). However, the likelihood of developing PD with inherited LRRK2 pathogenic variants differs (a phenomenon known as “reduced penetrance”), with factors including age and geographic region, highlighting a potential role for lifestyle and environmental factors in disease onset. To investigate this, household dust samples from four different groups of individuals were analyzed using metabolomics/exposomics and metagenomics approaches: PD+/LRRK2+ (PD patients with pathogenic LRRK2 variants; n = 11), PD-/LRRK2+ (individuals with pathogenic LRRK2 variants but without PD diagnosis; n = 8), iPD (PD of unknown cause; n = 11), and a matched, healthy control group (n = 11). The dust was complemented with metabolomics and lipidomics of matched serum samples, where available. A total of 1,003 chemicals and 163 metagenomic operational taxonomic units (mOTUs) were identified in the dust samples, of which ninety chemicals and ten mOTUs were statistically significant (ANOVA p-value