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[Preprint]. 2025 Sep 2:2025.08.28.25333987. [Version 1] doi: 10.1101/2025.08.28.25333987

The LRRK2 p.A419V variant associates with risk of Parkinson’s disease in the East Asian population and an evaluation on age of onset

Kai Shi Lim 1,2, Maria Teresa Periñan 3,4, Elaine Guo Yan Chew 5, Paul Suhwan Lee 6, Fulya Akçimen 7, Jia Lun Lim 8, Mathew J Koretsky 6, Manabu Funayama 9,10,11, Hiroyo Yoshino 10, Nobutaka Hattori 9, Rauan Kaiyrzhanov 12,13, Henry Houlden 12, Mariam Isayan 14, Yi Wen Tay 1,2, Tzi Shin Toh 2,8, Lei-Cheng Lit 15, Anis Nadhirah Khairul Anuar 15, Hans Xing Ding 15, Laurel Screven 16, Norlinah Mohamed Ibrahim 17, Chin-Hsien Lin 18, Han-Joon Kim 19, Jee-Young Lee 20, Sun Ju Chung 21, Jia Nee Foo 5, Eng-King Tan 22, Shen-Yang Lim 2,8, Ai Huey Tan 2,8,*, Sara Bandres-Ciga 6,*, Azlina Ahmad-Annuar 1,*; the Global Parkinson’s Genetics Program (GP2)
PMCID: PMC12424926  PMID: 40950508

Abstract

Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations. We investigated the p.A419V variant across multiple ancestry cohorts comprising over 200,000 individuals. In cases of East Asian ancestry, the variant was significantly associated with increased risk (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), It lies on rare EAS haplotypes, and was not in linkage disequilibrium with other LRRK2 coding variants. Although not significant, meta-analysis of age of onset in EAS cases show a suggestive trend (β = −0.89 years; SE = 1.01; p = 0.380). LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB10, RAB29 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling pathway.

Keywords: Parkinson’s disease, genetics, LRRK2, A419V, risk, age at onset, Asian

Introduction

Pathogenic variants in the LRRK2 gene, including p.R1067Q, p.N1437H, p.R1441G/C/H, p.Y1699C, p.G2019S and p.I2020T, are known to cause Mendelian forms of Parkinson’s disease (PD), and several were also identified as risk variants through genome-wide association studies (GWAS) and case-control analyses1–4. LRRK2 ‘Asian risk variants’, p.R1628P and p.G2385R, have been identified as key risk factors for sporadic PD in various Asian populations5,6.

Another LRRK2 variant, p.A419V (chr12:40252984:C>T, rs34594498, NM_198578.4:c.1256C>T), was first studied as a potential PD-associated variant in East Asians (EAS) from Taiwan7, where no significant association was found in a cohort of 608 cases and 373 controls. In a subsequent, larger combined EAS cohort from Japan, Korea, and Taiwan (1,376 cases; 962 controls), p.A419V was reported as a significant risk variant (odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.35 – 3.83; p = 0.0045)1. Several studies in EAS populations attempting to replicate this finding reported varied and inconsistent results8–12. In the most recent PD GWAS in EAS from mainland China, this variant reached suggestive genome-wide significance in both the discovery and replication cohorts (discovery: n = 1,972 cases, 2,478 controls; p = 2.47e-06, OR = 2.0; 95% CI = 1.33 – 3.03; replication: n = 8,209 cases, 9,454 controls; p = 2.64e-15, OR = 2.4; 95% CI = 1.90 – 2.90)13. EAS cohorts from 23andMe included in a multi-ancestry meta-analysis14 also showed a significant association between this variant and PD risk (n = 322 cases, 151,905 controls; OR = 3.2; 95% CI = 1.85 – 5.61; p = 0.0003).

In the broader Asian context, the p.A419V variant was not reported as significant in a case-control study from Kazakhstan in Central Asia (minor allele frequency, MAF n = 292 cases, 199 controls; OR = 1.5, p = 0.4)15. In South Asian cohorts, the p.A419V variant is rare with a MAF = 0.4% (n = 4,806 cases, 6,364 controls)16. The variant is absent in studies on Vietnamese (n = 83 early-onset PD (EOPD) cases17, and there is no available information from recent studies in Japan18 (n = 221 cases), Thailand19 (n = 47 EOPD cases), or Korea20 (GWAS n = 1,050 cases, 5,000 controls). This variant is absent/rare in European14,21 (n = 37,688 cases, 18,618 proxy-cases, 1.4 million controls; n = 49,049 cases, 18,785 proxy cases and 2,458,063 controls), African22 (GWAS n = 1,488 cases; 196,430 controls), Latin American23 (1,734 cases and 1,097 controls; Loesch et al., 2021, n = 807 cases and 690 controls), and North African Egyptian24 PD cohorts. These differences in LRRK2 p.A419V detection may be due to the higher allele frequency of p.A419V in EAS (MAF = 0.01028) compared to MAF < 0.001 in European, South Asian, and Middle East populations, and an even lower frequency in African populations (MAF < 0.0001), as reported in gnomAD v4.1.0 (exome + genome).

LRRK2 activity assays indicate that the p.A419V variant increases LRRK2-mediated Rab10Thr73 phosphorylation by more than 1.5-fold compared to wild-type, and moderately elevates the formation of LRRK2 filaments in the absence of MLi-2 treatment, consistent with other pathogenic LRRK2 variants25.

Despite evidence pointing to a potential deleterious effect of the LRRK2 p.A419V variant, inconsistent findings of variable significance across genetic association studies limited its inclusion in further functional characterization and clinico-genetic correlation efforts, particularly in comparison to the well-established EAS LRRK2 variants such as p.G2385R and p.R1628P26. The relevance of this variant in other PD populations was not fully studied. To address this gap while also increasing confidence for deep phenotyping and precision medicine applications, we leveraged large-scale genotyping data from the Global Parkinson’s Genetics Program (GP2), whole-genome sequencing (WGS) data from the Accelerating Medicines Partnership Parkinson’s Disease (AMP-PD)27,28, the UK Biobank (UKB, www.ukbiobank.ac.uk), and the All of Us Research Program (AOU, https://allofus.nih.gov/) in addition to whole-exome sequencing (WES) data from an EAS dataset29 and Juntendo University Hospital PD cohort. In addition, there is inconclusive evidence of the influence of Asian LRRK2 risk variants on age of onset30,31; therefore, this study sought to address this further for the p.A419V variant.

Methods

Cohorts under study

This study included six cohorts spanning multiple ancestries. Cohort 1 included genotyped data from GP2 release 9 (https://gp2.org/), comprising 25,699 unrelated PD patients and 13,652 controls from ten ancestry populations: European (EUR), East Asian (EAS), Admixed American/Latin American (AMR), Ashkenazi Jews (AJ), Central Asian (CAS), Complex Admixture History (CAH), Middle Eastern (MDE), South Asian (SAS), African American (AAC) and African (AFR) (Supplementary Table 1). Cohort 2 was composed of data from AMP-PD WGS release 3 (https://amp-pd.org/), which included 2,251 unrelated PD cases and 2,835 controls of European descent (Supplementary Table 1). Cohort 3 comprised individuals from the UKB (2,954 cases and 56,256 controls). Cohort 4 included data from the AOU Program (2,103 cases, 29,733 controls). Cohort 5 was an EAS-WES replication cohort (3,967 cases, 5,457 controls) described further below. Cohort 6 was a separate EAS cohort of Japanese ancestry (2,729 PD cases recruited from Juntendo University Hospital and 61,332 control individuals from the public database jMorp 61KJPN32, https://jmorp.megabank.tohoku.ac.jp/). Genotype comparisons in the Japanese population were conducted using R software, including a two-tailed Fisher’s exact test for calculation of OR for allele frequencies, and 95% CI.

Data Quality Control

Quality control (QC) of the GP2 data was performed using the GenoTools pipeline (https://github.com/GP2code/GenoTools)33. Briefly, samples were excluded if they had a genotyping rate below 95%, exhibited sex mismatches, or were duplicated (KINSHIP > 0.354), or displayed high heterozygosity (|F| statistic > 0.25). Variants were excluded if they had > 5% missingness, significant deviations from Hardy-Weinberg Equilibrium (HWE p < 1e-4), or non-random missingness based on case-control status (p ≤ 1e-4). Ancestry estimation was performed using Genotools33, with the default reference panels from the 1000 Genomes Project, the Human Genome Diversity Project, and Ashkenazi Jewish datasets. Additionally, individuals with second-degree or closer relatedness (KINSHIP > 0.0884) were removed before analysis. The percentage of ancestry was then calculated using the supervised functionality of ADMIXTURE (v1.3.0; https://dalexander.github.io/admixture/binaries/admixture_linux-1.3.0.tar.gz)34 with the same reference panel mentioned before to estimate the ancestry proportions of the GP2 data accurately.

Statistical analyses

The LRRK2 p.A419V variant was extracted from the raw genotyped NeuroBooster Array v1.0 (NBA)35 (Supplementary table 1) for GP2 data release 9 and from WGS data for AMP-PD version 3, the UKB, and the AOU.

LRRK2 p.A419V PD carriers and non-carriers were compared for sex and family history using the two-tailed Fisher’s exact test. Association between the LRRK2 p.A419V variant and PD risk was assessed by performing a logistic regression (glm) under an additive genetic model in PLINK 2.0 (Chang et al. 2015), where genotypes were encoded as 0 (homozygous major allele), 1 (heterozygous), and 2 (homozygous minor allele). Covariates, including sex, and the appropriate number of principal components (PCs) were included in the model. The number of PCs was determined by identifying the elbow point of the scree plot (Supplementary Figure 2) to account for population stratification (Supplementary Table 2)36. Additionally, allele and genotype frequencies, as well as HWE, were calculated using PLINK 2.0. Power calculation was performed using the GAS power calculator (https://csg.sph.umich.edu/abecasis/cats/gas_power_calculator/). The additive model was used with a significance level set at p = 0.05, PD general population prevalence of 0.5%21 at an OR of 2.27 according to the meta-analysis of this variant in the Asian population1 and an OR of 2.01 according to the largest Chinese GWAS study13. The association between p.A419V and age at onset (AAO) was assessed using a linear regression additive genetic model adjusted for sex and the appropriate number of PCs, as described above. Meta-analysis of AAO between GP2 EAS discovery cohort and EAS-WES replication cohort was analysed using R meta package37.

The EAS replication cohort consisted of published WES data from 3,967 PD patients and 5,457 ancestry- and geographically matched controls from five regions across East Asia [Singapore (SG): 1,955 cases, 3,630 controls; Malaysia (MAL): 325 cases, 59 controls; Hong Kong (HK): 70 cases, 586 controls; South Korea (KR): 1,417 cases, 1,040 controls; Taiwan (TW): 200 cases, 142 controls]29. A stratified Cochran-Mantel-Haenszel (CMH) test was used to evaluate the burden of LRRK2 p.A419V across the exomes of participants from the replication cohort. Fisher’s exact test (two-tailed) was used to assess the burden of LRRK2 p.A419V within each stratum. SG and MAL samples were considered as one stratum due to the similarity in genetic background.

Cohort 6 was a second EAS replication cohort of Japanese ancestry (2,729 PD cases recruited from Juntendo University Hospital with age of onset ≥ 21 and 61,000 control individuals from the public database jMorp 61KJPN32, https://jmorp.megabank.tohoku.ac.jp). Genotype comparisons in the Japanese population were conducted using R software, including a two-tailed Fisher’s exact test for calculation of odds ratios (OR) for allele frequencies, and 95% confidence intervals (CI).

Haplotype blocks in the GP2 EAS cohort were defined using the --block function in PLINK 1.9, with the minimum MAF threshold set to 0.0001 to allow the inclusion of LRRK2 p.A419V across all ancestries. Haplotype frequency estimation and association analysis were performed using the haplo.stats R package (version 1.9.7; https://cran.r-project.org/web/packages/haplo.stats/) under default settings. To further characterize the linkage disequilibrium (LD) structure, pairwise r2 values between LRRK2 p.A419V and all LRRK2 missense variants and other reported GWAS variants in the LRRK2 locus1–4,14,38,39 were calculated using PLINK 1.9.

LRRK2 protein structure prediction

The three-dimensional structures of LRRK2, and complexes with RAB8A, RAB10, RAB29, RAB32 were predicted using AlphaFold3 (https://hpc.nih.gov/apps/alphafold3/)40 on the NIH Biowulf high-performance computing cluster (https://hpc.nih.gov). FASTA sequences for each protein (LRRK2:Q5S007, RAB8A:P61006, RAB10:P61026, RAB29:O14966, RAB32:Q13637) were retrieved from UniProt (https://www.uniprot.org/)41, and subsequently AlphaFold3 input JSON files were generated. Multiple sequence alignments and model inference were performed to generate predicted protein structures. To improve the robustness of the predictions, five independent runs were initiated using different random seeds, and then the model with the best ranking score for each complex was selected for visualization using the PyMOL Molecular Graphics System, Version 3.0 Schrödinger, LLC.

Results

Overall data review

Demographics for each cohort separated by ancestry, including age at sample collection, age at onset, sex, and number of cases/controls, are presented in Supplementary Table 1. The LRRK2 p.A419V variant was in HWE across all ancestry groups in all the cohorts (Supplementary Table 4).

In the GP2 cohort, the LRRK2 p.A419V variant was found to be rare (MAF < 1%) across all populations (Table 1), with the highest frequency observed in the EAS (MAF = 1.3% cases, 0.36% controls), followed by CAS (MAF = 0.98% cases, 0.6% controls), CAH (MAF = 1.1% cases, none in controls), EUR (MAF = 0.12% cases, 0.02% controls), AJ (MAF = 0.03% cases, none in controls). In contrast, no carriers were observed in the AAC, AFR, AMR, MDE and SAS individuals. None of the cases were carriers in the EUR AMP-PD cohort, while the MAF in controls was 0.02%. In the UKB cohort, no carriers were identified in AAC, AFR, AMR, CAH, CAS, FIN, or MDE ancestry groups, while the MAF in EAS controls was 0.65% and no carriers were identified in the six EAS cases. The variant was present in UKB EUR individuals with MAF = 0.02% (cases) and MAF = 0.01% (controls). The MAF in the UKB SAS was 1.1% cases and 0.08% controls. In the AOU cohort, the highest number of carriers were of EAS (MAF = 6.60% cases, 0.40% controls), followed by EUR (MAF = 0.03% cases, 0.03% controls) and AMR (MAF = 0.01% controls, none in cases) ancestries. Thus, taking shared ancestries across the GP2, AMP-PD, UKB, and AOU cohorts, the EAS (MAF = 0.91%), CAS (MAF = 0.71%), CAH (MAF = 0.62%), SAS (MAF = 0.07%), EUR (MAF = 0.03%), AJ (MAF = 0.02%) (Table 1).

Table 1.

Frequency of the LRRK2 p.A419V variant across ancestries

Dataset Ancestry PD, n (%) breakdown in cohort Control, n (%) breakdown in cohort N Total Carriers AF Total (AC) N PD Carriers AF PD cases (AC) N Control Carriers AF controls (AC) AF gnomAD
GP2 25,699 cases; 13,652 controls AAC 338 (29.01) 827 (70.99) 0 0 (0/2330) 0 0 (0/676) 0 0 (0/1654) NA
AFR 983 (37.09) 1667 (62.91) 0 0 (0/5300) 0 0 (0/1966) 0 0 (0/3334) 0.00001334
AJ 1709 (67.47) 824 (32.53) 1 0.00020 (1/5066) 1 0.00029 (1/3418) 0 0 (0/1648) 0
AMR 2005 (58.4) 1428 (41.6) 0 0 (0/6866) 0 0 (0/4010) 0 0 (0/2856) 0.00006669
CAH 644 (67.51) 310 (32.49) 14 0.0073 (14/1908) 14 0.011 (14/1288) 0 0 (0/620) NA
CAS 661 (66.77) 329 (33.23) 17 0.0086 (17/1980) 13 0.0098 (13/1322) 4 0.006 (4/658) NA
EAS 3192 (57.3) 2379 (42.7) 97 0.0089 (99/11142) 81* 0.013 (82/6384) 16 * 0.0036 (17/4758) 0.01028
EUR 15332 (73.63) 5492 (26.37) 37 0.00094 (39/41648) 35 ^# 0.0012 (37/30664) 2 0.00018 (2/10984) 0.0001493
MDE 481 (70.94) 197 (29.06) 0 0 (0/1356) 0 0 (0/962) 0 0 (0/394) 0.0008267
SAS 354 (64.01) 199 (35.99) 0 0 (0/1106) 0 0 (0/708) 0 0 (0/398) 0.0001977
AMP-PD 2,835 cases; 2,251 controls EUR 2251 (44.26) 2835 (55.74) 1 0.000098 (1/10172) 0 0 (0/4502) 1 0.00018 (1/5670) 0.0001493
UKB 2,954 cases; 56,256 controls AAC 3 (2.21) 133 (97.79) 0 0 (0/272) 0 0 (0/6) 0 0 (0/266) NA
AFR 19 (4.11) 443 (95.89) 0 0 (0/924) 0 0 (0/38) 0 0 (0/886) 0.00001334
AJ 33 (7.42) 412 (92.58) 0 0 (0/890) 0 0 (0/66) 0 0 (0/824) 0
AMR 2 (4) 48 (96) 0 0 (0/100) 0 0 (0/4) 0 0 (0/96) 0.00006669
CAH 9 (5.08) 168 (94.92) 0 0 (0/354) 0 0 (0/18) 0 0 (0/336) NA
CAS 7 (3.32) 204 (96.68) 0 0 (0/422) 0 0 (0/14) 0 0 (0/408) NA
EAS 3 (1.91) 154 (98.09) 2 0.0064 (2/314) 0 0 (0/6) 2 0.0065 (2/308) 0.01028
EUR 2827 (4.98) 53963 (95.02) 10 0.000088 (10/113580) 1 0.00018 (1/5654) 9 0.000083 (9/107926) 0.0001493
MDE 6 (8.82) 62 (91.18) 0 0 (0/136) 0 0 (0/12) 0 0 (0/124) 0.0008267
SAS 45 (6.3) 669 (93.7) 2 0.0014 (2/1428) 1 0.011 (1/90) 1 0.00075 (1/1338) 0.0001977
AOU 2,103 cases, 29,733 controls AFR 144 (6.8) 5,884 (19.8) 0 0 (0/12052) 0 0 (0/288) 0 0 (0/11764) 0.00001334
AMR 231 (11) 3,877 (13) 1 1.22E-04 (1/8216) 0 0 (0/462) 1 0.0001 (1/7754) 0.00006669
EAS 15 (0.7) 748 (2.5) 8 0.005 (8/1526) 2 0.066 (2/30) 6 0.004 (6/1496) 0.01028
EUR 1,692 (80.4) 18,926 (63.7) 13 3.15E-04 (13/41236) 1 2.96E-04 (1/3384) 12 3.17E-04 (12/37852) 0.0001493
MDE 5 (0.2) 70 (0.2) 0 0 (0/150) 0 0 (0/10) 0 0 (0/140) 0.0008267
SAS 16 (0.8) 228 (0.8) 0 0 (0/488) 0 0 (0/32) 0 0 (0/456) 0.0001977
EAS-WES 3,967 cases; 5,457 controls EAS 3967 (42.09) 5457 (57.91) 177 0.0058 (180/18,848) 107” 0.0139 (110/7934) 70 0.0064 (70/10,914) 0.01028
JPN 2,729 cases; 61,332 controls EAS 2729 (4.26) 61332 (95.74) 2086 0.0165 (2107/128,112) 167 ` 0.0321 (175/5458) 1915 `` 0.0158 (1932/122,664) 0.01028
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AC = Allele Counts

AF = Allele Frequency

AF gnomAD = Population specific allele frequency in gnomAD 4.1

*

Include 1 homozygous carrier

^

Include 2 homozygous carriers

“

Include 3 homozygous carriers

`

Include 8 homozygous carriers

``

Include 17 homozygous carriers

#

22 out of 35 of these patients were submitted from Central Asia

AAC: African American or Caribbean, AFR: Sub-Saharan African, AJ: Ashkenazi Jewish, AMR: Admixed American, CAH: Complex Admixture History, CAS: Central Asian, EAS: East Asian populations, EUR: European, MDE: Middle Eastern, and SAS: South Asian.

Family history was not more commonly reported in LRRK2 p.A419V carriers (17.7%) compared to PD non-carriers across all ancestries, where it was reported in 25.2% of individuals (Table 1). A higher frequency of female LRRK2 p.A419V carriers was observed in the GP2 CAS and EUR groups (CAS: p = 0.008, 92.3% in carriers vs. 53.7% in non-carriers; EUR: p = 0.041, 54.6% in carriers vs. 37.7% in non-carriers) (Table 1).

Risk association analysis

Power calculations indicated that only the EAS and EUR cohorts in GP2 had an 80% power to detect an association with an OR > 2.0 and a p-value < 0.05 (Supplementary Table 3), while the AMP-PD, UKB, and AOU cohorts were underpowered for association analysis of the LRRK2 p.A419V variant.

Logistic regression analyses conducted in the GP2 EAS and EUR ancestry groups indicated that a significantly higher frequency of the LRRK2 p.A419V variant was observed in cases compared to controls in both the EAS (MAF cases = 1.15% vs. MAF controls = 0.57%; OR = 2.908; 95% CI = 1.659 – 5.098, p = 0.0002) and EUR (MAF cases = 0.06% vs. MAF controls = 0.02%; OR = 5.754; 95% CI = 1.399 – 23.66, p = 0.015) groups (Supplementary Table 5). The association in the EAS group was tested in the independent EAS cohort from the EAS exome dataset29. The LRRK2 p.A419V variant was present in 107 of 3,967 cases (1.4%) and 70 of 5,457 controls (0.6%), with a significant risk association (OR = 1.51, 95% CI =1.103 – 2.068, p = 0.012, Supplementary Table 6). In the Juntendo EAS-Japanese replication cohort, the p.A419V variant was significantly associated as a risk factor in Japanese PD patients (MAF = 3.20%) than in the controls (MAF = 1.58%); (OR = 2.06; 95% CI: 1.76 – 2.42; p = 1.301 × 10−16, Supplementary Table 6).

In the GP2 cohort, there was minimal LD (r2 < 0.01) between p.A419V and other LRRK2 coding variants across all ancestries studied (Supplementary Table 9), suggesting that the observed risk association is unlikely to be confounded by nearby coding variation. In addition, the LRRK2 p.A419V variant is not in LD with any lead SNPs identified in GWAS of PD in EAS populations4,14,38,39.

The LD block constructed around p.A419V consists of 8 SNPs (rs10506148, rs28365214, rs10878249, p.A211V, rs732374, p.V366M, p.L378F, rs1491938). Six rare haplotypes (MAF < 0.01) were identified in the GP2 EAS cohort, with one (Haplotype 9) observed in 1.2% PD cases and 0.34% controls (Supplementary Table 10), but further analysis lacked sufficient power to assess association. The haplotype analysis was not performed in the other EAS-WES dataset, as its exome sequencing data would not have fully contained sufficient variants to perform the LRRK2 haplotyping effectively. Additionally, the UKB and AOU cohorts had relatively small EAS sample sizes, limiting their utility for this analysis. No haplotype containing LRRK2 p.A419V was identified in the other GP2 ancestries due to the rarity of the variant.

Admixture analysis of the GP2 EUR cohort

As the comparatively higher allele frequency and risk association of the LRRK2 p.A419V in European individuals was unique to the GP2 EUR cohort - unlike the other EUR cohorts from AMP-PD, UKB, and AOU - carriers in this group were examined further. Based on ADMIXTURE analysis, the GP2 EUR LRRK2 p.A419V carriers were found to be highly admixed (Supplementary Table 7a), with 29/35 carriers having relatively lower EUR ancestry (median: 13.86%, range: 4.68% – 70.8%, Supplementary Table 7a) compared to EUR non-carriers (median: 65.75%, range: 4.09% - 82.30 %, Supplementary Table 7b). Notably, 22/35 carriers in the EUR ancestry group were Kazakhstani Central Asian patients. Therefore, these carriers may not be fully representative of the EUR ancestry group. In line with this, linear regression against percentage of genomic admixture in this group indicated that individuals who have less EUR ancestry are more likely to be LRRK2 p.A419V carriers (β = −0.23, SE = 1.78; p = 3.01e-19). In contrast, all the EAS p.A419V carriers demonstrated high EAS ancestry (median: 91.68%, range: 71.9% - 94.1%, Supplementary Table 7c) similar to EAS non-carriers (median: 91.83%, range: 44.24% - 94.91%, Supplementary Table 6d), lending greater confidence to the observed associations within this population.

Age at onset association analysis in EAS cohorts

Analysis of LRRK2 p.A419V carrier status and AAO in the GP2 EAS PD group (n=73 carriers, AAO 50.3 ± 12.6 years vs. n=2292 non-carriers, AAO 53.4 ± 12.7 years) (Table 3a), revealed an association with an earlier onset of PD by approximately 3 years (β = −3.02 years; SE = 1.49; p = 0.043) after adjusting for sex and 5 PCs (Figure 1). Six LRRK2 p.A419V carriers also carried a concomitant p.G2385R variant (mean AAO: 51.3 ± 13 years), and one patient with young onset, unknown monogenic PD status (AAO: 35 years) was found to have a concomitant p.R1628P variant (Supplementary Table 8). In the replication cohort, which included 103 LRRK2 p.A419V PD carriers and 3,557 non-carriers, linear regression adjusted for sex showed a similarly significant reduction in disease onset by approximately two and a half years (β = −2.79 years, SE = 1.03; p = 0.007). However, after additional adjustment for the first three PCs, the association was no longer statistically significant (β = −0.89 years; SE = 1.01; p = 0.380), despite the directionality of effect remaining consistent, with carriers showing a lower AAO (Table 2b). A fixed-effects meta-analysis combining the discovery and replication cohorts demonstrated a reduced but borderline-significant association (β = −1.55 years, SE = 0.83, p = 0.063; Supplementary Figure 3), supporting a modest effect of the variant on age at onset.

Figure 1: LRRK2 p.A419V and age at onset (Linear model).

Figure 1:

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Association of LRRK2 p.A419V with Age of onset were conducted using generalized linear models (GLM) with linear regression under an additive model.

Table 2:

Age at PD onset between LRRK2 p.A419V PD carriers and non-carriers in the GP2 cohort

Total AJ CAS CAH EUR EAS
p.A419V carrier non-carrier p-value p.A419V carrier non-carrier p-value p.A419V carrier non-carrier p-value p.A419V carrier non-carrier p-value p.A419V carrier non-carrier p-value p.A419V carrier non-carrier p-value
AAO, N 100 15189 2.526e-09 *** 1 1338 10 449 0.035 * 3 405 0.520 13 10705 0.357 73 2292 0.028 *
mean +− SD 50.29 +− 12.70 57.95 +− 12.40 45 62.37 +− 11.59 44.8 +− 11.85 52.8 +− 11.75 47.33 +− 17.67 53.93 +− 13.95 55.46 +− 12.93 58.74 +− 12.03 50.32 +− 12.56 53.41 +− 12.65
media n [IQR] 49 [20] 59 [18] 45 64 [16] 48.5 [16] 54 [16] 56 [16] 55 [19] 55 [16] 60 [16 .4] 49 [20] 52 [18]
FHX, n/N 14/79 4251/16848 0.142 0/0 484/1572 NA 1/11 58/505 1 2/4 100/504 0.181 3/11 2953/11610 0.356 8/53 656/2657 0.291
(%) 17.72 25.23 0 30.79 9.09 11.49 50 19.84 27.27 25.43 15.09 24.69
Male, n/N 57/141 11922/19675 0.000 *** 1/1 1125/1705 1 1/13 300/648 0.008 ** 4/14 365/630 0.052 15/33 9528/15288 0.041 * 37/81 1729/3109 0.087
(%) 40.43 60.59 100 65.98 7.69 46.3 28.57 57.94 45.45 62.32 45.68 55.61
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Mann Whitney U test was used for comparing age of onset difference between carrier and non-carrier groups

Fisher’s test was used for family history and sex comparison between carrier and non-carrier groups

n=Number of individuals with available information

N=Total number of individuals

IQR=Inter quartile range

FHX=Family history of PD

SD=Standard Deviation

AAO=Age at onset

AJ: Ashkenazi Jewish, CAH: Complex Admixture History, CAS: Central Asian, EAS: East Asian populations, EUR: European

*

P ≤ 0.05

**

P ≤ 0.01

***

P ≤ 0.001

The CAS ancestry in the GP2 cohort was observed to show a significant association with earlier AAO (β = −4.25 years; SE = 8.173; p = 0.011). However, given the small number of carriers in this group (n = 10), this should be interpreted cautiously. No significant association between LRRK2 p.A419V and AAO was observed in the CAH group (only present in the GP2 cohort), before or after adjusting for covariates.

Visualization of the predicted LRRK2 structure overlaid with known variants revealed that the p.A419V mutation resides within the ARM domain (amino acid position 12 – 704)42 (Figure 2A). Predicted structures of the LRRK2-RAB complexes demonstrated that the binding sites for RAB8A, RAB29, and RAB32 are spatially proximal to the p.A419V mutation site, consistent with experimental observations. Notably, the predicted binding site for RAB10 deviates from the ARM domain, despite experimental evidence suggesting similar binding motifs with other Rab proteins43,44.

Figure 2. Mutation sites and predicted Rab binding of LRRK2.

Figure 2.

Open in a new tab

Visualization of the predicted LRRK2 structure with different coloured domains (armadillo repeat (ARM) domain in brown/tan, ankyrin repeat (ANK) domain in pink, leucine-rich repeat (LRR) domain in blue, ROC (Ras of complex proteins) GTPase domain in yellow, COR (C-terminal of ROC) domain in orange, kinase domain in green, and the WD40 domain in red). The alanine residue at position 419, substituted by valine in the p.A419V variant, is indicated by a red sphere within the ARM domain.

Discussion

We investigated the genetic association between the LRRK2 p.A419V variant and PD risk and AAO, leveraging data across several cohorts, including the multi-ancestry GP2, AMP-PD, UKB, AOU cohorts, an EAS exome dataset and a Japanese dataset, totaling 40,287 PD cases and 168,681 controls. This study resolves inconsistencies in previous reports by providing robust evidence that the LRRK2 p.A419V is significantly associated with PD in both the EAS and EUR populations, with an approximate OR of 2.0. This is comparable with other LRRK2 risk variants in EAS populations, p.G2385R (OR ~ 2.3)45 and p.R1628P (OR ~ 1.8)46.

The variant is rare in EUR (MAF = 0.03%) and even rarer or absent in these AAC, AFR, AJ, AMR, FIN, and MDE populations’ samples. Compared to the other LRRK2 risk variants p.R1628P and p.G2385R (MAFs between 5–10% in cases and 2–5% in controls) (Lim et al. 2019), in the overall EAS cohorts in this study, the p.A419V variant is much less common (MAFTotal = 0.91%, MAFcases = 1.35% and MAFcontrols = 0.54%). Interestingly, this variant was also seen in other Asian populations, such as CAS (MAFTotal = 0.71%, MAFcases = 0.97% and MAFcontrols = 0.38%) and SAS (MAFTotal = 0.07%, MAFcases = 0.12% and MAFcontrols = 0.05%), compared to non-Asian populations, suggesting this variant may be more relevant to individuals of ‘East-Central-South’ Asian ancestries. The MAF seen in the SAS population in this study (0.07%) compares to 0.4% in a SAS GWAS by Kishore et al. 202516 (n=11,170), with gnomAD reporting an MAF of 0.02%. Thus far, the p.A419V variant has not been investigated as a risk variant in SAS populations. In CAS populations, a previous study found no significant association between the p.A419V variant and PD15, and this has also been observed in an unpublished extended sample set of 655 cases (MAF = 1.38%) and 528 controls (MAF = 0.85%) (personal communication, RK).

Only one LRRK2 p.A419V haplotype (Haplotype 9) was seen in both cases and controls, but association analysis for this haplotype is not possible due to its low frequency in both cases and controls. No disease-specific haplotype enrichment was observed. Haplotype analysis was not performed in the EAS-WES cohort due to limited variants from exome data.

Regarding the heritability of AAO concerning LRRK2 risk variants, a directionality towards an earlier AAO has been reported. Specifically, the combination of the p.G2385R-p.R1628P-p.S1647T variants was found responsible for lowering the AAO by approximately 8 years30. Regarding the LRRK2 p.A419V variant, a previous EAS study of 2,685 cases from mainland China did not find any association with an earlier AAO31. However, our study showed a modest effect on AAO in the GP2 EAS and EAS exome cohorts. We found LRRK2 p.A419V carriers developing PD approximately 3 years earlier than non-carriers, although we note the lack of robust association. A limitation of interpreting this result is the analysis of a single gene variant. Previous GWAS on AAO in European populations have identified variants in the TMEM175 and SNCA genes47 and BST148. Only two studies on AAO in the East Asian PD population were conducted. One was a meta-analysis of GWAS, which highlighted a SNP (rs9783733) in the novel NDN; PWRN4 locus, delaying AAO by 2.43 years, most significantly in male patients, as well as a suggestive signal in SNCA (rs3775458), which lowers AAO by 1.36 years49. In the other and more recent study, SNPs in LD with ALCAM were associated with an earlier AAO by 3.47 years in a Korean AAO-GWAS50. Additionally, polygenic risk scores (PRS) across multiple studies have shown a strong inverse correlation with AAO49–54. Thus, the contribution of the LRRK2 p.A419V variant on AAO will need to be evaluated more deeply in the context of other genome-wide genetic modifiers.

While an association with LRRK2 p.A419V was initially found in the GP2 EUR group, closer inspection of these carriers revealed that 22/35 of these patients were of Central Asian origin. As this variant is very rare in Europeans and in Central Europeans55 and its association with PD has not been reported in individuals of EUR ancestry despite multiple GWAS and LRRK2 studies4,14,21,56, we postulate that the association in our study may be an artefact due to inheritance of the LRRK2 p.A419V variant from the EAS/CAS chromosomal regions in these individuals. Resolution of admixture in the EUR-CAS individuals could be performed through local ancestry analysis. However, this was not currently possible as the number of control CAS genomes was insufficient. The issue of limited control individuals is not uncommon in underrepresented populations57 and presently poses a challenge in interpreting the contribution of rare variants such as p.A419V. Large-scale initiatives such as GP2, which is sequencing both PD cases and ancestry-matched controls, and existing or emerging national genome projects of several underrepresented populations contribute to bridging this gap. These include Kazakhstan (Central Asia)58–60, China (East Asia)61, Singapore (Southeast Asia)62, and the Americas6,63. Future efforts will play a crucial role in providing a more accurate interpretation of disease-relevant genomic variants.

The alanine residue at position 419 in LRRK2 is highly conserved (ConSurf score 9/9), suggesting that mutations at this site may significantly alter protein function. The p.A419V variant lies within the LRRK2 armadillo repeat domain (ARM), which mediates the interaction between LRRK2 and multiple Rab GTPases43,64,65. Thus, facilitating recruitment of LRRK2 to intracellular vesicle trafficking pathways, including the trans-Golgi network and endolysosomal system66–69. Recent studies indicate that the variant is located in a distinct region in the ARM domain, termed site #1 (encompassing amino acids 360–450), which is reported to be the precise binding site of RAB29, RAB8A, and RAB1043,44. Together, the Rab substrates anchor LRRK2 to membranes, enabling it to acquire a more active state through enhanced GTPase phosphorylation, in a proposed ‘feed-forward pathway’44,70. Cells carrying variants neighbouring p.A149V, p.L403A, and p.K439E interfere with optimal binding of Rab8A and Rab29 substrates44 and recently the p.[L119P;L488P] variants were also shown to affect the binding affinity of RAB8A71, and it could be postulated that the p.A419V variant may have similar effects. However, this has yet to be demonstrated and would be best addressed with in vitro and in vivo models.

Through LRRK2 protein modelling with Alphafold3, the predicted model with the available regions of the X-ray structure as published in Myasnikov et al., 202142, yielded acceptable agreement (RMSD = 0.992), underscoring the value of the predicted model for visualizing the ARM domain. The predicted interaction interfaces between LRRK2 and RAB proteins placed the p.A419V variant in close proximity to the binding regions for RAB8A, RAB29, and RAB32, which tallies with experimental data43,44. However, while these predictions offer valuable insights, they are inherently limited in defining the precise binding sites. The deviation observed for RAB10, whose predicted site lies outside of the ARM domain, may arise due to the AlphaFold3 model itself and/or the possibility that LRRK2 exists as a dimer during RAB protein interactions. Although these limitations exist, the predicted structures are useful for visualization and will guide future structural and functional investigations, particularly as current X-ray structures lack the ARM domain. This finding suggests if the p.A419V variant causes conformational changes to LRRK2, this may have an effect on binding affinity to RAB proteins through the ARM domain, and this may lead to disrupted LRRK2-RAB signaling.

In conclusion, the LRRK2 p.A419V variant is a rare but significant risk factor for PD in EAS individuals. Further research on this variant, along with LRRK2 p.R1628P and p.G2385R, is needed to gain a more comprehensive understanding of the genetic architecture of EAS PD populations. In the emerging era of LRRK2-directed treatments, this study highlights that variants in the ARM domain, the site of several RAB substrate binding, may be a rare but relevant target for further clinical, biomarker, and therapeutic studies.

Supplementary Material

Supplementary Table: Supplementary table

Supplementary Figure: Supplementary figure

Acknowledgements

We gratefully acknowledge all the participants for their contributions, without whom this research would not have been possible. Data and code used to prepare this article were obtained from the Global Parkinson’s Genetics Program (GP2). GP2 is funded by the Aligning Science Across Parkinson’s (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson’s Research (https://gp2.org). For a complete list of GP2 members, see https://gp2.org. Data used to prepare this article were obtained from the Accelerating Medicines Partnership® (AMP®) Parkinson’s Disease (AMP® PD) Knowledge Platform. For up-to-date information on the study, visit https://www.amp-pd.org. ACCELERATING MEDICINES PARTNERSHIP and AMP are registered service marks of the US Department of Health and Human Services. We thank the research participants for consenting to this study. Additionally, data used in this article were obtained from the UK Biobank, the All of Us Research Program, an East Asian whole-exome dataset, and a Japanese whole-exome dataset. This research has been conducted using the UK Biobank Resource under Application Number 33601.

The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276. In addition, the All of Us Research Program would not be possible without the partnership of its participants.

This research was supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

Financial Disclosure

AH Tan received speaker honoraria from Eisai and Orion Pharma, and research grants from the Michael J Fox Foundation. MJK’s participation in this project was part of a competitive contract awarded to DataTecnica LLC by the National Institutes of Health to support open science research.

Funding statement

This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services; project number ZO1 AG000535 and ZIA AG000949, as well as the National Institute of Neurological Disorders and Stroke (NINDS) and the National Human Genome Research Institute (NHGRI). Data used in the preparation of this article were obtained from the Global Parkinson’s Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinson’s (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson’s Research. Additional funding was provided by The Michael J. Fox Foundation for Parkinson’s Research through grant MJFF-009421/17483. The AMP® PD program is a public-private partnership managed by the Foundation for the National Institutes of Health and funded by the National Institute of Neurological Disorders and Stroke (NINDS) in partnership with the Aligning Science Across Parkinson’s (ASAP) initiative; Celgene Corporation, a subsidiary of Bristol-Myers Squibb Company; GlaxoSmithKline plc (GSK); The Michael J. Fox Foundation for Parkinson’s Research; Pfizer Inc.; Sanofi US Services Inc.; and Verily Life Sciences. The Singapore East Asian work was supported by the Singapore Ministry of Health’s National Medical Research Council Open Fund Large Collaborative Grant (MOH-000207; to E.-K.T), Open Fund Individual Research Grant (MOH-000559; to J.N.F.), as well as the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE-T2EP30220-0005; to J.N.F.) and Tier 3 (MOE-MOET32020-0004; to J.N.F.).

Funding Statement

This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services; project number ZO1 AG000535 and ZIA AG000949, as well as the National Institute of Neurological Disorders and Stroke (NINDS) and the National Human Genome Research Institute (NHGRI). Data used in the preparation of this article were obtained from the Global Parkinson’s Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinson’s (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson’s Research. Additional funding was provided by The Michael J. Fox Foundation for Parkinson’s Research through grant MJFF-009421/17483. The AMP® PD program is a public-private partnership managed by the Foundation for the National Institutes of Health and funded by the National Institute of Neurological Disorders and Stroke (NINDS) in partnership with the Aligning Science Across Parkinson’s (ASAP) initiative; Celgene Corporation, a subsidiary of Bristol-Myers Squibb Company; GlaxoSmithKline plc (GSK); The Michael J. Fox Foundation for Parkinson’s Research; Pfizer Inc.; Sanofi US Services Inc.; and Verily Life Sciences. The Singapore East Asian work was supported by the Singapore Ministry of Health’s National Medical Research Council Open Fund Large Collaborative Grant (MOH-000207; to E.-K.T), Open Fund Individual Research Grant (MOH-000559; to J.N.F.), as well as the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE-T2EP30220-0005; to J.N.F.) and Tier 3 (MOE-MOET32020-0004; to J.N.F.).

Footnotes

Ethical considerations

SingHealth Centralized Institutional Review Board (CIRB 2002/008/A and 2019/2334) and Nanyang Technological University Institutional Review Board (IRB-2016-08-011)

Ethics committee of Juntendo University, Tokyo, Japan, and all participants provided written informed consent to participate in the research described in this study (M08‐0477‐M09)

International Genetics Collaboration (IGC) CI: Prof H Houlden Sponsor EDGE ID: 146653 REC Ref: IRAS: 310045 Protocol V1.1 22/06/2022

Declaration of conflicting interest

The authors declared no potential conflicts of interest for the research, authorship, and/or publication of this article.

Data availability

All GP2 data is hosted in collaboration with the Accelerating Medicines Partnership in Parkinson’s disease, and is available via application on the website (https://amp-pd.org/register-for-amp-pd;https://doi.org/10.5281/zenodo.7904832). Genotyping imputation, quality control, ancestry prediction, and processing was performed using GenoTools v1.0, publicly available on GitHub (https://github.com/GP2code/GenoTools). https://github.com/AAA-lab-genetic/Multiancestry_LRRK2_p.A419V)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All GP2 data is hosted in collaboration with the Accelerating Medicines Partnership in Parkinson’s disease, and is available via application on the website (https://amp-pd.org/register-for-amp-pd;https://doi.org/10.5281/zenodo.7904832). Genotyping imputation, quality control, ancestry prediction, and processing was performed using GenoTools v1.0, publicly available on GitHub (https://github.com/GP2code/GenoTools). https://github.com/AAA-lab-genetic/Multiancestry_LRRK2_p.A419V)

Articles from medRxiv are provided here courtesy of Cold Spring Harbor Laboratory Preprints

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