Objective: To construct a polygenic risk score (PRS) for Multiple system atrophy (MSA), investigate its associations with a broad range of phenotypes in the UK Biobank, and assess potential causal relationships
Background: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by autonomic failure, parkinsonism, and cerebellar ataxia. However, there is a lack of systematic exploration of the association between genetic susceptibility and a wide spectrum of phenotypes.
Method: Using summary statistics from the 2024 MSA GWAS by Chia et al. (888 cases, 7,128 controls) and data from 407,908 European ancestry participants in the UK Biobank, we constructed an MSA-PRS with PRSice-2. Phenome-wide association analysis was performed using PHESANT across 4,743 phenotypes in nine categories, with false discovery rate correction. Significant phenotypes were further evaluated by two-sample MR.
Results: The optimal MSA-PRS was obtained at a P-value threshold of 0.0768, explaining approximately 0.6% of variance (p = 2.1 × 10⁻⁵). MSA-PRS was significantly higher in patients with MSA than in healthy controls and patients with Parkinson’s disease (both p = 0.022), supporting a partially distinct genetic architecture. PheWAS identified 33 phenotypes significantly associated with MSA-PRS, including fluid intelligence, fruit and vegetable preference, dried fruit and cheese intake, fed-up feelings, self-rated health, abdominal pain, symptomatic medication use, alkaline phosphatase, educational attainment, and occupational characteristics. MR supported inverse causal associations of educational attainment (A/AS levels: OR = 0.06; college/university degree: OR = 0.25), household income (OR = 0.32), and cheese intake (OR = 0.40) with MSA risk, and positive associations for poorer self-rated health (OR = 2.98) and leg fat percentage (OR = 1.76).
Conclusion: MSA genetic susceptibility is associated with multidimensional phenotypes spanning cognition, diet, health, biochemistry, and socioeconomic factors. These findings provide new insights into MSA pathogenesis and potential targets for risk stratification and prevention.
To cite this abstract in AMA style:
XH. Chen, JW. Chen, W. Luo. Polygenic Risk Score-Based Phenome-Wide Association Study and Mendelian Randomization of Multiple System Atrophy in the UK [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/polygenic-risk-score-based-phenome-wide-association-study-and-mendelian-randomization-of-multiple-system-atrophy-in-the-uk/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/polygenic-risk-score-based-phenome-wide-association-study-and-mendelian-randomization-of-multiple-system-atrophy-in-the-uk/