Elucidating the Multitrait Association between Parkinson’s Disease and Respiratory Disorders: HLA gene complex as a causal nexus

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Abstract Background Respiratory disorders are gaining recognition as common comorbidities in Parkinson's disease (PD) patients, and these comorbidities have significant implications for PD patient outcomes and mortality. However, the genetic basis and potential causal relationships between PD and respiratory dysfunction remain unclear. Understanding these associations could provide insights into shared pathophysiological mechanisms and identify potential therapeutic targets. Method We conducted a genetic association study using large-scale genome-wide association study (GWAS) summary data for PD (n = 482,730), lung function (n = 321,047), chronic obstructive pulmonary disease (COPD; n = 325,027), idiopathic pulmonary fibrosis (IPF;n = 953,873), obstructive sleep apnoea (OSA;n = 159,255) and asthma (n = 1,376,071) in individuals of European ancestry. We employed Mendelian randomization (MR), colocalization and summary data-based Mendelian randomization (SMR) analysis to evaluate potential causal relationships and identify shared genetic loci. Besides, we conductedsingle-cell RNA sequencing (scRNA-seq) and enrichment analysis to investigate cell type-specific gene expression patterns and their potential roles in PD and respiratory disorders. Result MR indicates that obstructive ventilatory dysfunction predicts greater motor impairment, whereas restrictive ventilatory dysfunction predicts cognitive decline in PD. Genetically predicted PD increases IPF risk (odds ratio [OR] = 1.14) and reduce the risk of OSA (OR = 0.97). Colocalization identifies 26 loci with shared causal variants; the HLA-DQA1 and HLA-DQB1 genes emerge as key candidates. SMRlinks coupled with expression quantitative trait loci from lung, blood and brain regions demonstrates that altered expression of these genes is associated with disease risk. Single-cell RNA sequencing of peripheral blood mononuclear cells and substantia nigra pars compacta samples shows distinct expression patterns of HLA-DQA1 and HLA-DQB1 in B cells, T cells and microglia from patients with PD and COPD. Enrichment analyses implicate major histocompatibility complex class II binding, T-cell activation and pro-inflammatory cytokine production. Conclusion We conducted a multitrait analysis focusing on PD and respiratory disorder traits, and further identified two shared causal variants that are prioritized between these traits. These findings suggest that shared genetic mechanisms underlie PD and respiratory disorders, highlighting the potential immunomodulatory role of the HLA gene complex and its interactome in mediating these associations.

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