Association of LRRK2 Haplotype With Age at Onset in Parkinson Disease

Genetic factors provide valuable clues to the pathogenesis of Parkinson disease (PD), owing to their roles in disease development. Mutations in 9 genes have been conclusively linked to monogenic PD over the past 2 decades.¹ Among Asian populations, the S1647T, R1628P, and G2385R variants of LRRK2 are established risk factors for PD.² Clinically, patients who have these LRRK2 risk variants share substantial similarities with patients with sporadic PD. It has been suggested that the G2385R variant is associated with a lower age at onset (AAO) of PD.³ However, it is unknown whether the presence of multiple LRRK2 risk variants modulates the AAO of PD. We hypothesize that increases in the genetic burden of LRRK2 risk variants may be associated with a younger AAO. To test this hypothesis, we conducted a correlation study among a cohort of participants with PD who carried the LRRK2 risk variants S1647T, R1628P, and G2385R.

A total of 1284 patients with PD were assessed at the movement disorder outpatient clinics at the National Neuroscience Institute. The clinical diagnosis was based on the UK PD Brain Bank criteria.⁴ Our study was approved by the SingHealth Centralised institutional review board. Written informed consent was obtained from all of the participants. Clinical data collected included age, AAO, race/ethnicity, sex, and family history of PD. The LRRK2 variants S1647T, R1628P, and G2385R were genotyped by TaqMan (Thermo Fisher Scientific) real-time polymerase chain reaction. Ten percent of the results (n = 129) were selected for Sanger sequencing to check for errors. The concordance rate of the 2 genotyping methods in this study was 100%. The AAO of carriers and noncarriers of LRRK2 variant(s) was compared using a 2-sample t test and a Wilcoxon rank sum test, and statistical significance was set at P<.05.

Among the patients with PD, the mean (SD) AAO was 62.3 (10.8) years, with women (63.3 [10.3] years) developing PD later than men (61.6 [11.2] years) (95% CI, 0.49-2.90; P = .006). A total of 495 participants had no S1647T, R1628P, or G2385R variant, while 789 participants carried at least 1 of these risk variants. Because all 92 R1628P and all 84 G2385R carriers also had S1647T, the group of patients who carried a single variant was the same group who carried the S1647T variant but neither of the other 2 variants. The mean (SD) AAO of participants with no risk variants was 62.5 (10.5) years. By comparison, with 1 risk variant, the mean (SD) AAO was 62.3 (10.9) years (95% CI, −1.35 to 1.18; P = .90), while with 2 variants (R1628P + S1647T or G2385R + S1647T) the mean (SD) AAO was 61.3 (11.2) years (95% CI, −0.70 to 3.15; P = .21) and with all 3 variants (S1647T, R1628P, and G2385R) the mean (SD) AAO was 52.6 (12.3) years (95% CI, 3.29-16.51; P = .004) (Figure). The difference in the AAO between the carriers with all 3 variants and the noncarriers remained significant after adjusting the significance level for multiple testing using the Bonferroni correction to P < .05 / 3 = .02. A Wilcoxon test comparing participants who carried 3 risk alleles vs noncarriers yielded P = .02, which was also significant at the Bonferroni-corrected level of 0.02. Among the 10 participants who carried all 3 variants, 4 (40%) developed PD before age 50 years, while only 51 participants (10.3%) in 495 noncarriers reported their first PD-related complaint before 50 years. A further analysis conducted among an independent Asian cohort⁵ of 465 patients from Malaysia was used to substantiate our results. We identified 4 patients who had all 3 risk alleles in the Malaysian cohort. The AAO values for these 4 participants were 45, 49, 57, and 59 years, respectively, with a mean (SD) AAO of 52.5 (5.7) years, which was lower than the 60.1 (11.0) for noncarriers. The 7.6-year difference was comparable with the 8.7 years in our cohort, although the P values from a 2-sample t test (P = .10) and a Wilcoxon rank sum test (95% CI, −3.24 to 18.35; P = .11) were of borderline significance because of the smaller sample size.

In this study, we examined the association of LRRK2 risk variants with the AAO of PD. Our data show that the presence of multiple risk variants in a patient with PD may significantly lower the AAO of PD. These LRRK2 variants are located in the genetic coding regions and may potentially alter protein function. The R1628P and S1647T variants are located in the C terminal of Ras of complex proteins domain, whereas the G2385R variant is located in the WD40 domain.⁶ Thus, these coding variants may contribute to PD development through distinct mechanisms and additively lower the AAO of PD. Our data suggest that increases in the genetic burden of LRRK2 variants may be associated with an earlier AAO in PD.

Corresponding Author: Eng-King Tan, MD, Department of Neurology, Singapore General Hospital, Outram Road, Singapore 169608 (gnrtek@sgh.com.sg).

Published Online: November 13, 2017. doi:10.1001/jamaneurol.2017.3363

Author Contributions: Drs Xiao and Tan had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Xiao, Tan.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Xiao, Deng, Ng, Tan.

Critical revision of the manuscript for important intellectual content: Xiao, Allen Jr, Lim, Ahmad-Annuar, Tan.

Statistical analysis: Xiao, Deng, Allen Jr, Tan.

Obtained funding: Tan.

Administrative, technical, or material support: Xiao, Ng, Lim, Ahmad-Annuar, Tan.

Supervision: Tan.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by the STaR and Translational Clinical Research Programme in Parkinson’s Disease grants from the National Medical Research Council (Dr Tan).

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.