Objective: To determine if the presence of the Asian LRRK2 risk variants (G238R, S1647T, R1628P) confers an increased risk in developing PD in a Singaporean cohort when future risk is determined using the MDS prodromal PD criteria.

Background: The MDS prodromal PD criteria models the likelihood of future PD development by combining its risk factors and prodromal markers. Genetic mutations have been described in monogenic forms of PD. In sporadic PD, polygenic risk factors have been implicated in PD risk in the West. In Asia, LRRK2 polymorphic variants were associated with an increased PD risk. To the best of our knowledge, ours is the first study to investigate whether the LRRK2 polymorphic variants seen in Asians increases the risk of future PD when risk is estimated using the MDS prodromal PD criteria.

Method: Healthy subjects were recruited from the community. Demographic, genotyping, cognitive, non-motor, motor and imaging assessments were performed to derive the Likelihood Ratio (LR) using the MDS prodromal PD criteria. Subjects were classified as a LRRK2 Risk Carrier if they had at least 1 Asian LRRK2 risk variant or a LRRK2 Non-Risk Carrier if they did not carry any LRRK2 risk variants.

Results: 174 subjects were recruited (M=50%; 63.28±5.09 years). 111 subjects were LRRK2 Risk Carriers (M=48.65%; 63.26±5.09 years) and 63 subjects were LRRK2 Non-Risk Carriers (M=52.38%; 63.27±5.09 years) (p=0.64; p=0.47). At baseline, the mean LR for LRRK2 Risk Carriers was 7.01% and 8.87% for LRRK2 Non-Risk Carriers (p=0.46).

The statistically significant markers that had the greatest contribution to the LR were First degree relative with PD (LR+ 9.77%, p=0.015), Type II Diabetes mellitus (LR+ 4.6%, p=0.003), Physical inactivity (LR+ 9.77%, p=0.045), Low plasma urate (LR+ 1.15%, p=0.002), Possible RBD (LR+ 6.32%, p=0.01), Excessive Daytime Somnolence (LR+ 4.60%, p=0.004) and Symptomatic Orthostatic Hypotension (LR+ 9.2%, p=0.013).

Conclusion: Our results showed that when comparing the Asian LRRK2 Risk Carriers and Non-Carriers at baseline, there was no difference in the final post-test probability when derived using the MDS prodromal PD criteria. Possible reasons include: 1) Asians LRRK2 risk variants have a small predictive value on future PD risk. 2) The MDS prodromal PD criteria may not be applicable to the Asian LRRK2 Risk Carriers.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/asian-lrrk2-variants-do-not-increase-likelihood-ratios-derived-from-mds-prodromal-parkinsons-disease-criteria-in-a-community-population/