LRRK2 variant spectrum and association study in a multi-ethnic cohort of Malaysian Parkinson’s disease patients

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Abstract The variant spectrum of LRRK2 in the multi-ancestry Malaysian population remains largely uncharacterized. In this study, 2,034 Parkinson’s disease (PD) patients and 1,059 controls (Malays, Chinese, Indians and Indigenous) were screened. Seventy-seven heterozygous non-synonymous variants were identified, including four known pathogenic/likely pathogenic variants (p.R1067Q, p.R1325Q, p.R1441C/H) and three risk alleles (p.A419V, p.R1628P, p.G2385R). There were 51 variants of uncertain significance (VUS), including two high-interest VUS (p.A1413T, p.P1446L) and five novel VUS (p.L162F, p.D523N, p.F877S, p.E1566D, p.D1858A). In the Chinese cohort, the p.G2385R variant was significantly associated with increased PD risk by 3.2-fold. After Bonferroni correction, the p.R1628P risk allele and the p.N551K-p.R1398H-p.K1423K protective haplotype associations were not significant. Double heterozygous p.R1628P-p.G2385R patients were observed to have a mean age at diagnosis (AAD) of 54.4 ±12.1 years while non- LRRK2 carriers had a mean AAD of 59.0 ±12.0 years. Domain-based low-frequency and rare variant tests highlighted the WD40 domain, largely driven by the p.G2385R variant, as disease-relevant for the Chinese subgroup. Overall, this study offers the most comprehensive catalog of LRRK2 variation in the Malaysian population to date, providing a valuable resource for future genetic studies of Southeast Asian ancestries, and aiding in the development of relevant LRRK2 -targeted therapies.

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