Background

The death of dopaminergic neurons in the substantia nigra tissue is considered to play a vital role in the development of Parkinson’s disease (PD). The classic symptoms of PD include a range of movement (or motor) features such as tremor, stiffness, slowness of movement and balance issues. These motor symptoms are believed to be linked to the loss of dopaminergic neurons in the substantia nigra. It is also essential to recognise that non-movement (or non-motor) symptoms such as loss of smell, depression, REM sleep behaviour, and cognition are also common in Parkinson’s, and can significantly impact an individual’s quality of life. Some of these non-motor symptoms have been previously linked to functional changes in the brain cortex tissue. In addition to the motor and non-motor symptoms of PD, several traits can co-occur with PD—for example, migraine and visual impairment, among many others. However, little is known about the mechanisms underlying associations between PD and co-occurring traits, including non-motor features.

Therefore, a group led by Prof. Justin O’Sullivan at the Liggins Institute, University of Auckland, in collaboration with Dr Antony Cooper from Garvan Institute of Medical Research, have conducted research to identify genetic risk factors of PD in the brain cortex tissue. Our team has also developed an approach that utilises multi-omics data to efficiently identify the co-occurring traits of PD without requiring prior information on co-morbid/co-occurring conditions.

What are the main findings from this study?

We identified 19 genes in the brain cortex whose expression changes were causally linked to PD through Mendelian Randomization, a statistical technique that utilises genetic variants as instrumental variables to infer causal relationships between an exposure (here, gene expression) and outcome (i.e. PD). Additionally, we found genes whose expression changes were associated with single nucleotide polymorphisms (SNPs) discovered by genome-wide association studies (GWAS) conducted on PD, indicating a potential contribution of altered gene expression in the brain cortex to PD risk.

Further analysis using multi-omics datasets, including protein-protein interaction networks, expression quantitative loci, and GWAS Catalog data, revealed 62 traits that may co-occur with PD. These traits encompass established PD-associated co-morbid conditions such as worry, vitamin D levels, and melanoma. This finding indicates molecular interactions between genes regulated by SNPs associated with the 62 traits and PD-risk or PD-associated genes, shedding light on the mechanisms underlying their co-occurrence.

We also found that genes and their regulatory loci on chromosome 17q21.31 underlie the association between PD and non-motor traits, including depressed affect, worry, and neuroticism. The 17q21.31 loci has previously been strongly implicated in various neurodegenerative diseases and our findings add further support to this growing body of knowledge.

Why are these findings significant?

Non-motor symptoms often manifest during the prodromal (or early) stage of PD before the onset of motor symptoms. Our research has identified genetic risk factors that may contribute to the co-occurrence of PD and non-motor traits, offering mechanistic insights into their associations. These genetic risk factors have the potential to serve as biomarkers, guiding stratification in the design of clinical trials aimed at targeting therapies for non-motor symptoms of PD. Moreover, incorporating this knowledge as an a priori element during trial design will be a critical step towards reducing initial failure rates and adopting a precision medicine approach to PD treatment.