Parkinson's disease genome-wide association study-linked PARK16 variant is associated with a lower risk of cognitive impairment: A 4-year observational study.

BACKGROUND AND PURPOSE: A genome-wide association study-linked variant (PARK16 rs6679073) modulates the risk of Parkinson's disease (PD). We postulate that there may be differences in clinical characteristics between PARK16 rs6679073 carriers and noncarriers. In a prospective study, we investigate the clinical characteristics between PARK16 rs6679073 A allele carriers and noncarriers over 4 years. METHODS: A total of 204 PD patients, comprising 158 PARK16 rs6679073 A allele carriers and 46 noncarriers, were recruited. All patients underwent motor and nonmotor symptom and cognitive assessments yearly over 4 years. RESULTS: PARK16 rs6679073 carriers were less likely to have mild cognitive impairment (MCI) compared to noncarriers at both baseline (48.1% vs. 67.4%, p = 0.027) and 4-year follow-up (29.3% vs. 58.6%, p = 0.007). CONCLUSIONS: PD PARK16 rs6679073 carriers had significantly lower frequency of MCI in a 4-year follow-up study, suggesting that the variant may have a neuroprotective effect on cognitive functions.

Alzheimer's Disease-Associated SNP rs708727 in SLC41A1 May Increase Risk for Parkinson's Disease: Report from Enlarged Slovak Study.

SLC41A1 (A1) SNPs rs11240569 and rs823156 are associated with altered risk for Parkinson's disease (PD), predominantly in Asian populations, and rs708727 has been linked to Alzheimer's disease (AD). In this study, we have examined a potential association of the three aforementioned SNPs and of rs9438393, rs56152218, and rs61822602 (all three lying in the A1 promoter region) with PD in the Slovak population. Out of the six tested SNPs, we have identified only rs708727 as being associated with an increased risk for PD onset in Slovaks. The minor allele (A) in rs708727 is associated with PD in dominant and completely over-dominant genetic models (ORD = 1.36 (1.05-1.77), p = 0.02, and ORCOD = 1.34 (1.04-1.72), p = 0.02). Furthermore, the genotypic triplet GG(rs708727) + AG(rs823156) + CC(rs61822602) might be clinically relevant despite showing a medium (h ≥ 0.5) size difference (h = 0.522) between the PD and the control populations. RandomForest modeling has identified the power of the tested SNPs for discriminating between PD-patients and the controls to be essentially zero. The identified association of rs708727 with PD in the Slovak population leads us to hypothesize that this A1 polymorphism, which is involved in the epigenetic regulation of the expression of the AD-linked gene PM20D1, is also involved in the pathoetiology of PD (or universally in neurodegeneration) through the same or similar mechanism as in AD.

Parkinson's disease GWAS-linked Park16 carriers show greater motor progression.

BACKGROUND: Data on the long-term motor outcomes of genome-wide association study (GWAS)-linked Parkinson disease (PD) carriers are useful for clinical management. OBJECTIVES: To characterise the association between GWAS-linked PARK16 gene variant and disease progression in PD over a 9-year time frame. METHODS: Over a 9-year period, carriers of PARK16 rs11240572 variant and non-carriers were followed up and evaluated using the modified Hoehn and Yahr (H&Y) staging scale and Unified Parkinson's Disease Rating Scale (UPDRS) part III. A longitudinal, linear mixed model was performed to compare the changes of H&Y staging scale, UPDRS motor score and UPDRS subscores between the two groups. RESULTS: A total of 156 patients (41 PARK16 carriers and 115 non-carriers) were evaluated and followed up for up to 9 years. Using longitudinal linear mixed model analysis, there was a greater rate of deterioration in the motor function as measured by the UPDRS scores compared with non-carriers after 5 years from the date of diagnosis (p=0.009). In addition, we demonstrated that PARK16 variant carriers had worse gait scores (p=0.043) and greater motor progression than non-carriers after 6 years based on the modified H&Y staging scale (p=0.040). CONCLUSIONS: In a 9-year longitudinal study, we demonstrated that PD PARK16 variant carriers exhibited greater motor progression after 5 years of disease compared with non-carriers, suggesting that GWAS-linked gene variants may influence disease progression over time. Closer monitoring and management of these higher risk patients can facilitate a better quality of life.

SNPs rs11240569, rs708727, and rs823156 in SLC41A1 Do Not Discriminate Between Slovak Patients with Idiopathic Parkinson's Disease and Healthy Controls: Statistics and Machine-Learning Evidence.

Gene SLC41A1 (A1) is localized within Parkinson's disease-(PD)-susceptibility locus PARK16 and encodes for the Na+/Mg2+-exchanger. The association of several A1 SNPs with PD has been studied. Two, rs11240569 and rs823156, have been associated with reduced PD-susceptibility primarily in Asian populations. Here, we examined the association of rs11240569, rs708727, and rs823156 with PD in the Slovak population and their power to discriminate between PD patients and healthy controls. The study included 150 PD patients and 120 controls. Genotyping was performed with the TaqMan® approach. Data were analyzed by conventional statistics and Random Forest machine-learning (ML) algorithm. Individually, none of the three SNPs is associated with an altered risk for PD-onset in Slovaks. However, a combination of genotypes of SNP-triplet GG(rs11240569)/AG(rs708727)/AA(rs823156) is significantly (p < 0.05) more frequent in the PD (13.3%) than in the control (5%) cohort. ML identified the power of the tested SNPs in isolation or of their singlets (joined), duplets and triplets to discriminate between PD-patients and healthy controls as zero. Our data further substantiate differences between diverse populations regarding the association of A1 polymorphisms with PD-susceptibility. Lack of power of the tested SNPs to discriminate between PD and healthy cases render their clinical/diagnostic relevance in the Slovak population negligible.

PARK16 is associated with PD in the Malaysian population.

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.

Patterns of linkage disequilibrium at PARK16 may explain variances in genetic association studies.

BACKGROUND: Reproducing genomewide association studies findings in different populations is challenging, because the reproducibility fundamentally relies on the similar patterns of linkage disequilibrium between the unknown causal variants and the genotyped single-nucleotide polymorphisms (SNPs). METHODS: The PARK16 locus was reported to alter the risk of Parkinson's disease (PD) in genomewide association studies in Japanese and Caucasians. We evaluated the regional linkage disequilibrium pattern at PARK16 locus in Caucasians, Japanese, and Chinese from HapMap and Chinese, Malays, and Indians from the Singapore Genome Variation Project, using the traditional heatmaps and targeted analysis of PARK16 gene via Monte Carlo simulation through varLD scores of these ethnic groups. RESULTS: One hundred SNPs in Caucasians, 95 SNPs in Chinese, 78 SNPs in Japanese from HapMap, 86 SNPs in Chinese, 99 SNPs in Indians, and 97 SNPs in Malays from the Singapore Genome Variation Project were included. Our targeted analysis showed that the linkage disequilibrium pattern of SNPs close to rs947211 was similar in Caucasians and Asians, including Chinese, Japanese, and Malay (all P > 0.0001), whereas different linkage disequilibrium patterns around rs823128, rs823156, and rs708730 were found between Caucasians and these Asian groups (all P < 0.0001). CONCLUSIONS: Our study suggests a higher chance to detect the association between rs947211 and PD in Chinese, Malay, and other Caucasian groups because of the similar linkage disequilibrium pattern around rs947211. The associations between rs823128/rs823156/rs708730 and PD are more likely to be replicated in Chinese and Malay populations.

The effect of the PARK16 rs11240572 variant on brain structure in Parkinson's disease.

Increasing evidence suggests that genetic factors play a key role in the development of Parkinson's disease (PD). The variant rs11240572 in the PARK16 gene locus is strongly associated with PD. However, its effect on the pathogenesis of PD is yet to be clarified. The objective of the study was to explore the effect of the PARK16 rs11240572 variant on brain structure in PD patients. A total of 51 PD patients were enrolled in the study and genotyped for the rs11240572 variant. Clinical assessments and MRI scans were conducted across all participants. Voxel-based morphometry (VBM) was used to investigate gray matter volume (GMV) of the whole brain between these two groups. Correlation analysis was performed to identify the relationships between GMV and clinical features. There were 17 rs11240572-A variant carriers and 34 non-carriers, with no significant demographic differences between these two groups. Compared with non-carriers, rs11240572-A carriers showed increased GMV in the left caudate nucleus and putamen, but decreased GMV in the left superior temporal gyrus and supramarginal gyrus. In non-carriers, left basal ganglia GMV was positively correlated with UPDRS III (r = 0.365, p = 0.034) and bradykinesia (r = 0.352, p = 0.042), but negatively correlated with MMSE (r = - 0.344, p = 0.047), while in carriers negative correlation between basal ganglia GMV and MMSE was also observed (r = - 0.666, p = 0.004). Moreover, the GMV of left temporoparietal cortex was positively associated with cognitive function in both groups (carriers, r = 0.692, p = 0.002; non-carriers, r = 0.879, p < 0.001). When reducing the sample size of non-carriers to the level of the carrier sample, similar correlations were observed in both groups. Our study showed that the PARK16 rs11240572 variant affects the brain structure of patients with PD, especially in the basal ganglia and temporoparietal cortex. This indicated that this variant might play an important role in the pathogenesis of PD.

Methylation quantitative trait locus analysis of chronic postsurgical pain uncovers epigenetic mediators of genetic risk.

Background: Overlap of pathways enriched by single nucleotide polymorphisms and DNA-methylation underlying chronic postsurgical pain (CPSP), prompted pilot study of CPSP-associated methylation quantitative trait loci (meQTL). Materials & methods: Children undergoing spine-fusion were recruited prospectively. Logistic-regression for genome- and epigenome-wide CPSP association and DNA-methylation-single nucleotide polymorphism association/mediation analyses to identify meQTLs were followed by functional genomics analyses. Results: CPSP (n = 20/58) and non-CPSP groups differed in pain-measures. Of 2753 meQTLs, DNA-methylation at 127 cytosine-guanine dinucleotides mediated association of 470 meQTLs with CPSP (p < 0.05). At PARK16 locus, CPSP risk meQTLs were associated with decreased DNA-methylation at RAB7L1 and increased DNA-methylation at PM20D1. Corresponding RAB7L1/PM20D1 blood eQTLs (GTEx) and cytosine-guanine dinucleotide-loci enrichment for histone marks, transcription factor binding sites and ATAC-seq peaks suggest altered transcription factor-binding. Conclusion: CPSP-associated meQTLs indicate epigenetic mechanisms mediate genetic risk. Clinical trial registration: NCT01839461, NCT01731873 (ClinicalTrials.gov).

Association of ZNF184, IL1R2, LRRK2, ITPKB, and PARK16 with sporadic Parkinson's disease in Eastern China.

BACKGROUND: Genetic factors may play important roles in the pathogenesis of Parkinson's disease, and more than 40 loci involved in Parkinson's disease have been identified. Due to differing allele frequencies across origins, the associations of these loci and sporadic Parkinson's disease in the Eastern Chinese population are still unclear. OBJECTIVE: The aim of this study was to investigate the relationship between 20 single nucleotide polymorphisms and Parkinson's disease in the Eastern Chinese population. METHODS: A total of 441 Parkinson's disease patients and 384 healthy controls were recruited. The MassARRAY System was used to detect 20 single nucleotide polymorphisms. Odds ratios (OR) were calculated to assess the relationship between polymorphisms and Parkinson's disease susceptibility. RESULTS: We found that ITPKB rs4653767 (OR [95 % confidential interval (CI)] = 0.524 [0.309-0.922], p =  0.023), ZNF184 rs9468199 (OR [95 % CI] = 0.530 [0.326-0.862], p =  0.010), IL1R2 rs34043159 (OR [95 % CI] = 0.794 [0.651-0.968], p =  0.022), LRRK2 rs76904798 (OR [95 % CI] = 0.397 [0.225-0.700], p = 0.001), and PARK16 rs11240572 (OR [95 % CI] = 0.715 [0.531-0.962], p =  0.027) were significantly associated with Parkinson's disease. CONCLUSIONS: LRRK2 rs76904798, ZNF184 rs9468199, PARK16 rs11240572, ITPKB rs4653767, and IL1R2 rs34043159 may associate with Parkinson's disease in the Eastern Han Chinese population.

Association between rs823128 polymorphism and the risk of Parkinson's disease: A meta-analysis.

Numerous published case-control studies have investigated a role of PARK16 gene in susceptibility to Parkinson's disease (PD), but the results remain conflicting and under-powered. Herein, we performed this meta-analysis to evaluate the possible association between the polymorphism of the PARK16 rs8231128 (A/G) and PD.A comprehensive search of six databases was conducted to identify all case-control studies involving PARK16rs823128variants and PD risk up to August 2017. The strict inclusion and exclusion criteria were applied. A total of 9 studies including 15 case-control studies with 7277 PD cases and 6188 controls were included in the meta-analysis. And STATA 12.0 statistics software was used to calculate available data from each study. The crude odds ratios (OR) and 95% confidence interval (CI) were calculated to assess the genetic association between PARK16 rs823128 polymorphism and the risk of PD. In the combined analysis, results showed a significant association between rs823128 and PD in allelic model(G vs. A: OR=0.886, 95% CI=0.811-0.969, P=0.008), dominant model (GG+ AG vs. AA: OR=0.886, 95% CI=0.804-0.976, P=0.014), and heterozygote model (AG vs. AA: OR=0.897, 95% CI=0.812-0.991, P=0.032). Further, ethnicity based analysis showed a significant association in Asian and Chilean population, but not in Caucasian samples. Within its limitations, this meta-analysis demonstrated that the rs823128 variants(G allele, GA and GG genotype)in PARK16 might be a potential protective factor for PD. However, these associations vary in different ethnicities.

Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study.

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted.

Association between PARK16 and Parkinson's disease: A meta-analysis.

Recent years, several case-control studies reported that two polymorphisms (rs947211 and 1572913) within the PARK16 locus were associated with the Parkinson's disease (PD). However, the results were still controversial. Herein, we conducted a comprehensive meta-analysis to estimate the associations between two polymorphisms and PD. Seven databases (PubMed, Google Scholar, EMBASE, Web of Science, CNKI (China National Knowledge Infrastructure), VIP and Wanfang) were searched to identify the eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the associations of two polymorphisms with PD susceptibility. Totally, 15 studies with 6637 cases and 6774 controls were included in our meta-analysis. The results showed that rs947211 variants were associated with a decreased risk of PD in overall population. Stratified analysis found that rs947211 variants were associated with a significantly decreased risk of PD in Northeast Asian population, but a slightly decreased risk of PD in Southeast Asian and Caucasian population. With regard to rs1572913 polymorphism, the results suggested that rs1572913 variants contribute to decrease the risk of PD. Therefore, our meta-analysis suggested that rs947211 variants (A allele, AG and GG genotypes) may decrease the risk of PD in overall population, particularly in Northeast Asian population; and T allele, TC and TT genotypes of rs1572913 variants contributed to decrease the risk of PD.

Other Proteins Involved in Parkinson's Disease and Related Disorders.

In order to explain the molecular causes of Parkinson's Disease (PD) it is important to understand the effect that mutations described as causative of the disease have at the functional level. In this special issue, several authors have been reviewing the effects in PD and other parkinsonisms of mutations described in LRRK2, α-synuclein, PINK1-Parkin-DJ-1, UCHL1, ATP13A2, GBA, VPS35, FBOX7 and HTRA2. In this review, we compile the knowledge about other proteins with a more general role in neurodegenerative diseases (MAPT) or for which less data is available due to its recent discovery (EIF4G1, DNAJC13), the lack of structural or functional data (as for PLA2G6 or DNAJC6), or even their doubtful association with the disease (as for GIGYF2, SYNJ1 and SPR). Also the cellular pathways involved in this disease are reviewed, with the goal of having an overview of the effects on the proteins and its possible role in the disease. This knowledge could also serve as the basis for designing tools that may potentially be used as a treatment for the disease, such as inhibitory or activating molecules, as well as other involved in regulating the half-life of the proteins involved.

PARK16 polymorphisms, interaction with smoking, and sporadic Parkinson's disease in Japan.

Epidemiological evidence on the relationships between PARK16 single nucleotide polymorphisms (SNPs) and Parkinson's disease (PD) is inconsistent. We examined this issue in Japan. Included were 229 cases within six years of PD onset. Controls were 356 patients without neurodegenerative disease. Compared with subjects with the AA genotype of SNP rs823128, those with the AG genotype, but not the GG genotype, had a significantly reduced risk of sporadic PD. Compared with the AA genotype of SNP rs947211, both the AG genotype and the GG genotype were significantly related to an increased risk of sporadic PD. Using subjects with the AA genotype of SNP rs823156 as a reference group, there were significant inverse relationships under the additive and dominant models. No significant relationships were found between SNPs rs16856139 or rs11240572 and sporadic PD. The CAAAC, the TGAGA, and the CAGAC haplotypes were significantly related to sporadic PD. The additive interaction between SNP rs823128 and smoking affecting sporadic PD was significant, although the multiplicative interaction was not significant. The PARK16 SNPs rs823128, rs947211, and rs823156 and the CAAAC, TGAGA, and CAGAC haplotypes may be significantly associated with sporadic PD in Japan. New evidence of an additive interaction between SNP rs823156 and smoking is suggested.

Comprehensive promoter level expression quantitative trait loci analysis of the human frontal lobe.

BACKGROUND: Expression quantitative trait loci (eQTL) analysis is a powerful method to detect correlations between gene expression and genomic variants and is widely used to interpret the biological mechanism underlying identified genome wide association studies (GWAS) risk loci. Numerous eQTL studies have been performed on different cell types and tissues of which the majority has been based on microarray technology. METHODS: We present here an eQTL analysis based on cap analysis gene expression sequencing (CAGEseq) data created from human postmortem frontal lobe tissue combined with genotypes obtained through genotyping arrays, exome sequencing, and CAGEseq. Using CAGEseq as an expression profiling technique combined with these different genotyping techniques allows measurement of the molecular effect of variants on individual transcription start sites and increases the resolution of eQTL analysis by also including the non-annotated parts of the genome. RESULTS: We identified 2410 eQTLs and show that non-coding transcripts are more likely to contain an eQTL than coding transcripts, in particular antisense transcripts. We provide evidence for how previously identified GWAS loci for schizophrenia (NRGN), Parkinson's disease, and Alzheimer's disease (PARK16 and MAPT loci) could increase the risk for disease at a molecular level. Furthermore, we demonstrate that CAGEseq improves eQTL analysis because variants obtained from CAGEseq are highly enriched for having a functional effect and thus are an efficient method towards the identification of causal variants. CONCLUSION: Our data contain both coding and non-coding transcripts and has the added value that we have identified eQTLs for variants directly adjacent to TSS. Future eQTL studies would benefit from combining CAGEseq with RNA sequencing for a more complete interpretation of the transcriptome and increased understanding of eQTL signals.

Association between PARK16 and Parkinson's disease in the Han Chinese population: a meta-analysis.

PARK16 was reported to alter the risk for Parkinson's disease (PD) in the Japanese population. However, its role in Han Chinese PD patients has not been well established. Herein, we investigated the effect of 4 single-nucleotide polymorphisms (SNPs) within the PARK16 locus, including rs823128, rs947211, rs823156, and rs11240572, on the risk of PD by genotyping 497 Taiwanese patients with PD and 500 age-matched control subjects. The results were then meta-analyzed with available genetic association studies in the same population. The meta-analysis showed that PD patients demonstrated a lower frequency of the rs823128 G allele (11.93%) than control subjects (14.04%; odds ratio [OR] 0.83, 95% confidence interval [CI] 0.72-0.96, p = 0.010). The frequency of the rs947211 A allele (40.35%) in PD patients was lower than in control subjects (43.01%; OR 0.90, 95% CI 0.80-0.99, p = 0.047). The rs823156 G allele was less frequently seen in PD patients (17.32%) than in control subjects (21.35%; OR 0.77, 95% CI 0.69-0.86, p < 0.001). A lower frequency of the rs11240572 A allele was found in PD patients (14.01%) than in control subjects (17.66%; OR 0.76, 95% CI 0.66-0.88, p < 0.001). Our results indicate a robust protective effect of PARK16 in Han Chinese PD patients. Functional approaches are needed to elucidate the effects of these SNPs on the regulation of gene expression.