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Determination of the longitudinal validity and minimally important difference of the 8-item Parkinson's Disease Questionnaire (PDQ-8)

Luo N, Tan LC, Zhao Y, Lau PN, Au WL, Li SC

Mov Disord, 2009 Jan 30;24(2):183-7.
PMID: 18972545 DOI: 10.1002/mds.22240

The aim of our study was to assess the longitudinal validity of the 8-item Parkinson's Disease Questionnaire (PDQ-8) in terms of responsiveness and test-retest reliability and to determine the minimally important difference (MID) for PDQ-8 using the anchor-based approach in Asians with Parkinson's disease (PD). A consecutive sample of PD patients attending a tertiary neuroscience clinic in Singapore completed the English or Chinese version of PDQ-8 twice during two different clinic visits. During the second visit, patients were also asked to rate their changes in health in general, PD severity, and overall impact of PD since at the time of their first visit 1 year ago using a 5-point response scale. A total of 96 patients participated in the study. For patients who reported changed conditions in the second visit, responsiveness measured by Cohen's effect size, standardized response mean, and Guyatt's responsiveness index ranged from 0.21 to 0.68. The intraclass correlation coefficient values calculated using patients reporting no change in health or PD status ranged from 0.64 to 0.76. The mean changed PDQ-8 summary index score in patients who reported that their health or PD status worsened only "a little bit" ranged from 5.8 to 7.4 points. Our current results show that PDQ-8 is a longitudinally reliable and responsive measure for assessing the health-related quality of life in patients with PD. The MID of the PDQ-8 estimated in the study will further support the use of this instrument in both clinical research and practice.
Evaluation of novel Parkinson's disease candidate genes in the Chinese population

Chew EGY, Liany H, Tan LCS, Au WL, Prakash KM, Annuar AA, et al.

Neurobiol Aging, 2019 02;74:235.e1-235.e4.
PMID: 30337193 DOI: 10.1016/j.neurobiolaging.2018.09.013

Recent whole-exome sequencing studies in European patients with Parkinson's disease (PD) have identified potential risk variants across 33 novel PD candidate genes. We aim to determine if these reported candidate genes are similarly implicated in Asians by assessing common, rare, and novel nonsynonymous coding variants by sequencing all 33 genes in 198 Chinese samples and genotyping coding variants in an independent set of 9756 Chinese samples. We carried out further targeted sequencing of CD36 in an additional 576 Chinese and Korean samples. We found that only 8 of 43 reported risk variants were polymorphic in our Chinese samples. We identified several heterozygotes for rare loss-of-function mutations, including the reported CD36 p.Gln74Ter variant, in both cases and controls. We also observed 2 potential compound heterozygotes among PD cases for rare loss-of-function mutations in CD36 and SSPO. The other reported variants were common in East Asians and not associated with PD, completely absent, or only found in controls. Therefore, the 33 reported candidate genes and associated variants are unlikely to confer significant PD risk in the East Asian population.
Fulltext Analysis of non-synonymous-coding variants of Parkinson's disease-related pathogenic and susceptibility genes in East Asian populations

Foo JN, Tan LC, Liany H, Koh TH, Irwan ID, Ng YY, et al.

Hum Mol Genet, 2014 Jul 15;23(14):3891-7.
PMID: 24565865 DOI: 10.1093/hmg/ddu086

To evaluate the contribution of non-synonymous-coding variants of known familial and genome-wide association studies (GWAS)-linked genes for Parkinson's disease (PD) to PD risk in the East Asian population, we sequenced all the coding exons of 39 PD-related disease genes and evaluated the accumulation of rare non-synonymous-coding variants in 375 early-onset PD cases and 399 controls. We also genotyped 782 non-synonymous-coding variants of these genes in 710 late-onset PD cases and 9046 population controls. Significant enrichment of LRRK2 variants was observed in both early- and late-onset PD (odds ratio = 1.58; 95% confidence interval = 1.29-1.93; P = 8.05 × 10(-6)). Moderate enrichment was also observed in FGF20, MCCC1, GBA and ITGA8. Half of the rare variants anticipated to cause loss of function of these genes were present in healthy controls. Overall, non-synonymous-coding variants of known familial and GWAS-linked genes appear to make a limited contribution to PD risk, suggesting that clinical sequencing of these genes will provide limited information for risk prediction and molecular diagnosis.
Fulltext Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study

Foo JN, Chew EGY, Chung SJ, Peng R, Blauwendraat C, Nalls MA, et al.

JAMA Neurol, 2020 06 01;77(6):746-754.
PMID: 32310270 DOI: 10.1001/jamaneurol.2020.0428

Importance: Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian).
Objectives: To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts.
Design Setting, and Participants: Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria.
Main Outcomes and Measures: Genotypes of common variants, association with disease status, and polygenic risk scores.
Results: Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10-12).
Conclusions and Relevance: This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.
Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson's disease risk

Chew EG, Liu Z, Li Z, Chung SJ, Lian MM, Tandiono M, et al.

Nat Aging, 2024 Nov 21.
PMID: 39572736 DOI: 10.1038/s43587-024-00760-7

Parkinson's disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10-15) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10-8). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease.