LRRK2 G2385R and R1628P Mutations Are Associated with an Increased Risk of Parkinson’s Disease in the Malaysian Population

Gopalai, Aroma Agape; Lim, Shen Yang; Chua, Jing Y i; Tey, Shelisa; Lim, Thien Thien; Ibrahim, Norlinah Mohamed; Tan, Ai Huey; Eow, Gaik Bee; Aziz, Zariah Abdul; Puvanarajah, Santhi Datuk; Shanthi, Vissa; Looi, Irene; Lim, Soo Kun; Tan, Li; Chong, Yip Boon; Tan, Chong Tin; Zhao, Yongxiang; Tan, Eng‐King; Ahmad‐Annuar, Azlina

doi:10.1155/2014/867321

Cited by 28 publications

(27 citation statements)

References 25 publications

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“…A recent paper looking at linkage disequilibrium (LD) using SNPs obtained from the Singapore Genome Variation Project has indicated that the LD pattern around the rs947211 SNP was similar to the pattern seen in the Caucasian and Asian (Chinese, Malay, and Japanese populations), compared to the other PARK16 SNPs [Li et al, ]. Given that PD genetics research has revealed possible ethnic‐specific variants in several genes such as the G2019S and G2385R variants in LRRK2 [Tan et al, ; Gopalai et al, ], it is interesting to note that the rs947211 SNP is shared amongst various ethnicities and has a common protective effect. Work by several groups have highlighted that a gain of function mutation (p.A350V) in the SLC41A1 gene in the PARK16 L ocus leads to intracellular changes in Magnesium chloride (Mg 2+ ) ions levels [Tucci et al, ; Yan et al, ; Kolisek et al, ].…”

Section: Discussionmentioning

confidence: 99%

PARK16 is associated with PD in the Malaysian population

Gopalai

Ahmad‐Annuar

et al. 2016

American J of Med Genetics Pt B

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PARK16 was identified as a risk factor for Parkinson's disease in a Japanese cohort; however, subsequent studies in the other populations including the Chinese, European, Caucasian, and Chilean have shown a protective role instead. To investigate this locus in our Malaysian cohort, 1,144 individuals were screened for five SNPs in the PARK16 locus and logistic regression analysis showed that the A allele of the rs947211 SNP reduced the risk of developing PD via a recessive model (Odds ratio 0.57, P-value 0.0003). Pooled analysis with other Asian studies showed that A allele of the rs947211 SNP decreased the risk of developing PD via a recessive model (Odds ratio 0.71, P-value 0.0001). In addition, when meta-analysis was performed with other Asian population, three SNPs (rs823128, rs823156, and rs11240572) reduced risk of developing PD via a dominant model. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

PARK16 is associated with PD in the Malaysian population

Gopalai

Ahmad‐Annuar

et al. 2016

American J of Med Genetics Pt B

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“…The NOS scores of all included studies ranged from 5 to 7 stars, indicating that they were studies of high methodological quality. Seven studies were carried out in China [8, 9, 14, 17–20], three in Singapore [7, 19], and six in Taiwan [7, 11–13, 19]; the remaining three studies were carried out in Malaysia [15], Thailand [10] and South Korea [16]. …”

Section: Resultsmentioning

confidence: 99%

Relationship between LRRK2 R1628P polymorphism and Parkinson's disease in Asian populations

Zhao

Kong

2016

Oncotarget

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Although the leucine-rich repeat kinase 2 (LRRK2) R1628P polymorphism has been associated with the risk of Parkinson's disease (PD) in Taiwan, China, and Singapore, there are conflicting findings regarding this relationship. Thus, the aim of the present meta-analysis was to evaluate the associations between the LRRK2 R1628P polymorphism (rs33949390) and PD in Asian populations. A search for eligible studies was performed in PubMed, Embase, SinoMed, and the China Knowledge Resource Integrated Database, and pooled odds ratios and 95% confidence intervals were used to evaluate the strength of the association between the R1628P polymorphism and PD. This meta-analysis assessed 19 studies from 14 papers that involved a total of 9,927 PD patients and 8,602 controls and found that the R1628P polymorphism was significantly associated with the risk of PD in Asian populations. Moreover, stratification analyses indicated that the R1628P polymorphism was significantly associated with an increased risk of PD among Chinese as well as non-Chinese Asian populations and an increased risk of PD in Chinese patients from China, Taiwan, and Singapore. In a stratified analysis conducted according to age, significant associations were found for both late-onset PD and early-onset PD. The present data indicate that the R1628P polymorphism of the LRRK2 gene contributes to PD susceptibility in Asian, especially Chinese, populations.

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“…5,6 The distribution of LRRK2 variants differs significantly among genetically diverse populations. 4,[7][8][9][10][11] The most commonly reported LRRK2 mutation, G2019S, accounts for~41% of PD in North African Arab-Berbers,~31% in Ashkenazi Jews with familial PD2, and is underrepresented in the Asian PD population. 7,12 Haplotype linkage disequilibrium studies suggest a common founder effect in these populations.…”

Section: Lrrk2mentioning

confidence: 99%

“…16 Similarly, the R1628P, A419V variants were associated with PD in Asian cohorts, whereas the M1646 T conferred risk in whites. 4,8,17,18 In a large East Asian cohort assessing nonsynonymous coding variations in the known PD genes, only variations in the LRRK2 were found to be enriched in PD patients. 19,20 Population-specific differences in the minor allele frequencies of the LRRK2 variants may contribute toward the relative significance of a particular variant in genetically diverse populations.…”

Section: Lrrk2mentioning

confidence: 99%

“…For instance, the G2385R variant is a risk factor in Asian subjects with PD, particularly ethnic Chinese with a population‐attributable risk of around 4% . Similarly, the R1628P, A419V variants were associated with PD in Asian cohorts, whereas the M1646 T conferred risk in whites . In a large East Asian cohort assessing nonsynonymous coding variations in the known PD genes, only variations in the LRRK2 were found to be enriched in PD patients .…”

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Understanding the role of genetic variability in LRRK2 in Indian population

et al. 2018

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Background Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. Objectives To resolve the role of LRRK2 in the Indian population. Methods We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. Results We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild‐type, the kinase domain variant showed 4‐fold increase in the kinase activity. Conclusions Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society

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LRRK2 G2385R and R1628P Mutations Are Associated with an Increased Risk of Parkinson’s Disease in the Malaysian Population

Cited by 28 publications

References 25 publications

PARK16 is associated with PD in the Malaysian population

PARK16 is associated with PD in the Malaysian population

Relationship between LRRK2 R1628P polymorphism and Parkinson's disease in Asian populations

Understanding the role of genetic variability in LRRK2 in Indian population

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