Objective: We aim to conduct a genome-wide survival study (GWSS) to identify single nucleotide polymorphisms (SNP) associated with dementia in Parkinson’s disease (PD) with a median duration of 10 years. Furthermore, we investigated the association between polygenic risk score (PRS) related to Alzheimer’s disease (AD), PD or amyloid deposition, and dementia in PD.

Background: Recent genome-wide association studies revealed genetic variants associated with PD susceptibility, but genetic variants for dementia in PD are under investigation. The PRS combines information from multiple genetic variants associated with a disease trait by summing up the weighted contributions of these genetic variants based on their effect sizes.

Method: We recruited patients with PD between 2009 and 2016 and performed genomic analysis using a Korean Chip, a customized microarray chip containing 827,783 SNP. After sample and variant quality control, and imputation, 7,570,000 SNPs were used for analysis. First, we conducted GWSS to estimate the genetic risk factor for dementia in PD. Evidence for genome-wide significance was defined as P≤5×10⁻⁸. Second, the association between PRS for PD, AD, and amyloid positivity and dementia in PD was evaluated with Cox proportional hazard models.

Results: Among the 964-study population, 225 patients were diagnosed with dementia after a median of 10 years of follow-up period. In GWSS, we found that SNPs rs201106258 in HS1BP3 (hazard ratio [HR] 8.00, 95% confidence interval [CI] 4.02−15.9, P=3.0×10⁻⁹) and rs56740294 in PTPRM genes (HR 3.58, 95% CI 2.29–5.60, P=2.5×10⁻⁸) in addition to rs429358 in APOE (HR 2.25, 95% CI 1.71–2.97, P=7.7 × 10⁻⁹) and rs10119 in TOMM40 genes (HR 2.18, 95% CI 1.67–2.85, P=1.0 × 10⁻⁸) were associated with dementia in PD. Asian AD-PRS (HR1.31, 95%CI 1.19−1.45, P<0.001) and European AD-PRS (HR1.89, 95%CI 1.23–2.91, P=0.004) were associated with an increased risk of dementia in PD. However, PD-PRS was not significantly associated with dementia in PD. PRS associated with amyloid positivity was associated with an increased risk of dementia in PD (HR, 2.07; 95% CI, 1.17–3.65, P=0.012).

Conclusion: We identified that SNPs in HS1BP3, PTPRM, APOE and TOMM40 genes as well as AD- and amyloid positivity-PRS were also associated with the development of dementia in PD. This could elucidate pathogenic mechanisms and therapeutic strategies for dementia in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-survival-analysis-identified-association-between-hs1bp3-and-apoe-loci-and-dementia-in-parkinsons-disease/