International Parkinson's Disease Genomics Research Articles

Investigating the causal and genetic relationship between migraine and Parkinson's disease.

The relationship between migraine and Parkinson's disease (PD) remains controversial. We aimed to investigate the causal and genetic associations between migraine and PD. Genetic data for migraine [any migraine (AM), migraine without aura (MO), and migraine with aura (MA)] and PD were sourced from the latest genome-wide meta-analyses conducted by the International Headache Genetics Consortium and the International Parkinson's Disease Genomics Consortium, respectively. Various analyses were performed to evaluate the potential causal associations and explore genetic correlations between these conditions. The analyses indicated that AM (odds ratio [OR] 1.02, 95% confidence interval [CI] 0.91-1.14; p = 0.785), MO (OR 0.94, 95% CI 0.84-1.07; p = 0.358), and MA (OR 1.01, 95% CI 0.95-1.06; p = 0.846) were not significantly associated with the risk of PD. Similarly, reverse analyses also demonstrated no significant causality between PD and the risks of migraine or its subtypes. After adjusting for coronary heart disease, AM (OR 0.99, 95% CI 0.90-1.10; p = 0.897), MO (OR 0.94, 95% CI 0.86-1.03; p = 0.207), and MA (OR 1.00, 95% CI 0.93-1.07; p = 0.902) remained unrelated to PD risk. Likewise, PD was found to be unassociated with AM (OR 0.96, 95% CI 0.92-1.02; p = 0.168), MO (OR 0.95, 95% CI 0.86-1.05; p = 0.287), and MA (OR 1.02, 95% CI 0.93-1.13; p = 0.669). These null findings persisted even when adjusting for hypertension. Apart from above causal inference results, no significant genetic correlation was found between AM (rg = -0.06, p = 0.127), MA (rg = -0.05, p = 0.516), or MO (rg = -0.06, p = 0.492) and PD, and no correlations were observed across specific genomic regions. Additionally, no shared heritability was observed between PD and migraine, or its subtypes, in tissue expression. Our study suggests that there is no significant causal association or genetic correlation between migraine and PD from a genetic perspective.

Causal association between Parkinson's disease and cancer: a bidirectional Mendelian randomization study.

Previous observational research has indicated a correlation between Parkinson's disease (PD) and multiple cancers; but the causality remains unclear. Thus, we utilized Mendelian randomization (MR) analysis to explore the potential causal link between PD and various cancers. We conducted a bidirectional two-sample Mendelian randomization (TSMR) of genetic variants associated with PD and 14 types of cancers. Summary statistics on PD and 14 types of cancers were obtained from the International Parkinson's Disease Genomics Consortium and the study by Sakaue et al. The primary method employed was inverse variance weighted (IVW), complemented by multiple sensitivity analyses to evaluate heterogeneity and pleiotropy. The false discovery rate (FDR) was employed to control the false positive rate of multiple hypothesis testing. Following rigorous sensitivity analyses and corrections, our findings revealed suggestive associations between PD and certain cancers. We observed that PD decreases the risk of gastric cancer and colorectal cancer (OR = 0.936, 95% CI = 0.881-0.995, p = 0.034, P FDR = 0.239; OR = 0.955, 95% CI = 0.912-0.999, p = 0.046, P FDR = 0.215), while increasing the risk of breast cancer (OR = 1.043, 95% CI = 1.004-1.084, p = 0.029, P FDR = 0.402). Notably, we found no evidence supporting a reverse causal relationship. Additionally, in the reverse pathway, skin cancer demonstrated a suggestive causal relationship with PD (OR = 0.913, 95% CI = 0.857-0.973, p = 0.005, P FDR = 0.066). Our MR analysis provides evidence supporting unidirectional suggestive causal relationships between PD and certain cancers. These findings enrich our comprehension of the intricate interplay between PD and cancer, warranting further investigation into the underlying biological mechanisms.

Risk of Parkinson's disease and depression severity in different populations: A two-sample Mendelian randomization analysis.

Depression is widely recognized as a common non-motor symptom of Parkinson's disease (PD). Across different studies, the reported prevalence of depression in PD varies widely, ranging from 2.7% to 90%, but it is unclear whether this association is due to genetic or acquired factors. Whether there is a causal relationship remains unknown. The aim of this study was to use a two-sample Mendelian randomization (MR) approach to investigate the causal effect of PD on depression. Analyses were conducted separately for individuals of European and East Asian ancestry using publicly available summary data from genome-wide association studies. Depression was divided into two categories: ever depressed for a whole week and major depressive disorder (MDD). PD data were used as the exposure and were obtained from the International Parkinson's Disease Genomics Consortium and the BioBank Japan PheWeb, while depression data were used as the outcome and were obtained from the ntegrative Epidemiology Unit (IEU) Open GWAS Project(A public GWAS database）and the Psychiatric Genomics Consortium. The influence of PD on depression was assessed using inverse variance weighted (IVW), weighted median, MR-Egger, and weighted mode methods. Heterogeneity and pleiotropy were tested, and the results were validated using FinnGen GWAS data from version R9. In individuals of European ancestry, there was a causal relationship between PD and ever depressed for a whole week (IVW method, odds ratio [OR]=0.990; 95% CI, 0.984-0.996; p=.002), but no causal relationship was observed between PD and MDD (IVW method, OR=0.974; 95% CI, 0.942-1.009; p=.141). In individuals of East Asian ancestry, no causal relationship was observed between PD and ever depressed for a whole week (IVW method, OR=1.001; 95% CI, 0.829-1.209; p=.990) and between PD and MDD (IVW method, OR=1.017; 95% CI, 0.982-1.052; p=.342). The results of the three additional analysis methods were similar to those of the IVW method, and there was no heterogeneity according to Cochran's Q-test. There was no evidence of pleiotropy based on MR-Egger intercept test and MR-PRESSO. The FinnGen validation dataset supported these findings. The results are stable and reliable. The observed increase in depression among PD patients could potentially be attributed to modifiable acquired factors. Consequently, there is an urgent need to strengthen the management of PD patients in order to prevent the development of depression in the future.

Cathepsins and Parkinson's disease: insights from Mendelian randomization analyses.

Parkinson's disease (PD), the second most prevalent neurodegenerative condition, has a multifaceted etiology. Cathepsin-cysteine proteases situated within lysosomes participate in a range of physiological and pathological processes, including the degradation of harmful proteins. Prior research has pointed towards a potential link between cathepsins and PD; however, the precise causal relationship between the cathepsin family and PD remains unclear. This study employed univariate and multivariate Mendelian randomization (MR) analyses to explore the causal relationship between the nine cathepsins and Parkinson's disease (PD) risk. For the primary analysis, genome-wide association study (GWAS) summary statistics for the plasma levels of the nine cathepsins and PD was obtained from the INTERVAL study and the International Parkinson's Disease Genomics Consortium. GWAS for PD replication analysis were obtained from the FinnGen consortium, and a meta-analysis was performed for the primary and replication analyses to evaluate the association between genetically predicted cathepsin plasma levels and PD risk. After identifying significant MR estimates, genetic co-localization analyses were conducted to determine whether shared or distinct causal variants influenced both cathepsins and PD. Elevated cathepsin B levels were associated with a decreased risk of PD in univariate MR analysis (odds ratio [OR] = 0.890, 95% confidence interval [CI]: 0.831-0.954, pFDR = 0.009). However, there was no indication that PD affected cathepsin B levels (OR = 0.965, 95% CI: 0.858-1.087, p = 0.852). In addition, after adjusting for the remaining cathepsins, cathepsin B levels independently and significantly contributed to the reduced risk of PD in multivariate MR analysis (OR = 0.887, 95% CI: 0.823-0.957, p = 0.002). The results of the replication MR analysis with the FinnGen GWAS for PD (OR = 0.921, 95% CI: 0.860-0.987, p = 0.020) and meta-analysis (OR = 0.905, 95% CI: 0.862-0.951, p < 0.001) were consistent with those of the primary analysis. Colocalization analysis did not provide any evidence of a shared causal variant between cathepsins and PD (PP.H4.abf = 0.005). This genetic investigation supports the hypothesis that cathepsin B exerts a protective effect against PD. The quantification of cathepsin B levels could potentially serve as a predictive biomarker for susceptibility to PD, providing new insights into the pathomechanisms of the disease and possible interventions.

Association between the sarcopenia-related traits and Parkinson's disease: A bidirectional two-sample Mendelian randomization study

ObjectiveTo explore the causal association between sarcopenia-related traits and Parkinson's disease by Mendelian randomization (MR) approach. MethodsA genome-wide association study (GWAS) of sarcopenia-related traits was done at the UK Biobank (UKB). The traits were appendicular lean mass, low hand grip strength (including the European Working Group on Sarcopenia in Older People (EWGSOP) and the Foundation for the National Institutes of Health (FNIH) criteria and usual walking pace. The International Parkinson's Disease Genomics Consortium (IPDGC) gave us GWAS data for Parkinson's disease (PD). We used three different types of MR analyses: including Inverse-variance weighted (IVW), Mendelian randomized Egger regression (MR-Egger), and weighted median methods (both weighted and simple modes). ResultsThe MR analysis showed that low hand grip strength was negatively associated with the risk of developing Parkinson's disease, including EWGSOP criterion (odds ratio (OR) = 0.734; 95% confidence interval (CI) = 0.575–0.937, P = 0.013) and FNIH criterion (OR = 0.619; 95% CI = 0.419–0.914, P = 0.016), and usual walking pace was also a risk factor for Parkinson's disease (OR = 3.307, 95% CI = 1.277–8.565, P = 0.014). ConclusionsIn European population, low hand grip strength is negatively associated with the risk of developing Parkinson's disease, and usual walking pace is also a risk factor for Parkinson's disease. Further exploration of the potential genetic mechanisms underlying hand grip strength and Parkinson's disease and the potential relationship between walking pace, balance, and falls in Parkinson's patients may help to reduce the burden of sarcopenia and Parkinson's disease.

Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study

An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations. We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity. We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10-14) and age at onset at the GBA1 locus, rs3115534-G (age at onset β=-2·00 [SE=0·57], p=0·0005, for African ancestry; and β=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity. Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease. The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research.

Associations between gut microbiota and Parkinson disease: Abidirectional Mendelian randomization analysis.

Parkinson disease (PD)-associated alterations in the gut microbiome have been observed in clinical and animal studies. However, it remains unclear whether this association reflects a causal effect in humans. We performed two-sample bidirectional Mendelian randomization using summary statistics from the international consortium MiBioGen (N = 18,340), the Framingham Heart Study (N = 2076), and the International Parkinson's Disease Genomics Consortium for PD (33,674 cases and 449,056 controls) and PD age at onset (17,996 cases). Twelve microbiota features presented suggestive associations with PD risk or age at onset. Genetically increased Bifidobacterium levels correlated with decreased PD risk (odds ratio = 0.77, 95% confidence interval [CI] = 0.60-0.99, p = 0.040). Conversely, high levels of five short-chain fatty acid (SCFA)-producing bacteria (LachnospiraceaeUCG010, RuminococcaceaeUCG002, Clostridium sensustricto1, Eubacterium hallii group, and Bacillales) correlated with increased PD risk, and three SCFA-producing bacteria (Roseburia, RuminococcaceaeUCG002, and Erysipelatoclostridium) correlated with an earlier age at PD onset. Gut production of serotonin was associated with an earlier age at PD onset (beta = -0.64, 95% CI = -1.15 to -0.13, p = 0.013). In the reverse direction, genetic predisposition to PD was related to altered gut microbiota composition. These results support a bidirectional relationship between gut microbiome dysbiosis and PD, and highlight the role of elevated endogenous SCFAs and serotonin in PD pathogenesis. Future clinical studies and experimental evidence are needed to explain the observed associations and to suggest new therapeutic approaches, such as dietary probiotic supplementation.

Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors.

ObjectiveThe aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual‐level genetic data available.MethodsWe calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership–Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome‐wide association study meta‐analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene‐based analyses and functional enrichment analyses.ResultsA higher polygenic resilience score was associated with a lower risk for PD (β = −0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome‐wide significance, MAGMA gene‐based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow‐sense heritability associated with resilience to PD (h 2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.InterpretationThe present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high‐risk genetic burden from developing PD. ANN NEUROL 2022;92:270–278

Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease.

ObjectiveParkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex‐specific manner.MethodsIn an effort to study sex‐specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta‐analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases.ResultsIn total, 19 genomewide significant regions were identified and no sex‐specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%).InterpretationWe did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. ANN NEUROL 2021;90:41–48

Assessment of ANG variants in Parkinson's disease

Genetic risk factors are occasionally shared between different neurodegenerative diseases. Previous studies have linked ANG, a gene encoding angiogenin, to both Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Functional studies suggest ANG plays a neuroprotective role in both PD and amyotrophic lateral sclerosis by reducing cell death. We further explored the genetic association between ANG and PD by analyzing genotype data from the International Parkinson's Disease Genomics Consortium (14,671 cases and 17,667 controls) and whole genome sequencing data from the Accelerating Medicines Partnership - Parkinson's disease initiative (AMP-PD, https://amp-pd.org/) (1,647 cases and 1,050 controls). Our analysis did not replicate the findings of previous studies and identified no significant association between ANG variants and PD risk.

Tumor Necrosis Factor Inhibition and Parkinson Disease: A Mendelian Randomization Study.

ObjectiveTo evaluate the effects of long-term tumor necrosis factor (TNF) inhibition on the risk and age at onset of Parkinson disease (PD), we performed a 2-sample Mendelian randomization study using genome-wide association studies (GWAS) summary statistics.MethodsGenetic variants in the vicinity of TNFRSF1A, the gene encoding TNF receptor 1 (TNFR1), were identified as predictive of pharmacologic blockade of TNFR1 signaling by anti-TNF therapy, based on genetic associations with lower circulating C-reactive protein (CRP; GWAS n = 204,402). The effects of TNF-TNFR1 inhibition were estimated for PD risk (ncases/controls = 37,688/981,372) and age at PD onset (n = 28,568) using GWAS data from the International Parkinson's Disease Genomics Consortium and 23andMe, Inc. To validate variants as proxies of long-term anti-TNF treatment, we also assessed whether variant associations reflected anticipated effects of TNFR1 inhibition on Crohn disease, ulcerative colitis, and multiple sclerosis risk (n = 38,589-45,975).ResultsTNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio [OR] per 10% lower circulating CRP = 0.99; 95% confidence interval [CI] 0.91–1.08) or age at onset (0.13 years later onset; 95% CI −0.66 to 0.92). In contrast, genetically indexed TNF-TNFR1 signaling blockade predicted reduced risk of Crohn disease (OR 0.75; 95% CI 0.65–0.86) and ulcerative colitis (OR 0.84; 95% CI 0.74–0.97) and increased multiple sclerosis risk (OR 1.57; 95% CI 1.36–1.81). Findings were consistent across models using different genetic instruments and Mendelian randomization estimators.ConclusionsOur findings do not imply that TNF-TNFR1 signaling inhibition will prevent or delay PD onset.Classification of EvidenceThis study provides Class II evidence that TNF-TNFR1 signaling inhibition is not associated with the risk or age at onset of PD.

Replication assessment of NUS1 variants in Parkinson's disease

The NUS1 gene was recently associated with Parkinson's disease (PD) in the Chinese population. Here, as part of the International Parkinson's Disease Genomics Consortium, we have leveraged large-scale PD case-control cohorts to comprehensively assess damaging NUS1 variants in individuals of European descent. Burden analysis of rare nonsynonymous damaging variants across case-control individuals from whole-exome and -genome data sets did not find evidence of NUS1 association with PD. Overall, single-variant tests for rare (minor allele frequency<0.01) and common (minor allele frequency>0.01) variants, including 15 PD-GWAS cohorts and summary statistics from the largest PD GWAS meta-analysis to date, also did not uncover any associations. Our results indicate a lack of evidence for a role of rare damaging nonsynonymous NUS1 variants in PD in unrelated case-control cohorts of European descent, suggesting that the previously observed association could be driven by extremely rare population-specific variants.

Association between telomere length and Parkinson's disease: a Mendelian randomization study

In this study, we examined the potential association of telomere length with Parkinson's disease (PD) using the publicly available genome-wide association study summary statistics from the International Parkinson's Disease Genomics Consortium involving up to 37,688 patients with PD and 449,056 controls in Mendelian randomization framework. The Mendelian randomization approach has the potential to investigate a causal relationship between a risk factor and a disease, avoiding confounding and reverse causation that often present in conventional epidemiological studies. We did not find that longer telomeres were associated with higher risks of PD (odds ratio: 1.18, 95% confidence interval: 0.94, 1.48, p = 0.15). Our study, therefore, did not provide evidence to support a potential causal relationship between telomere length and PD.

The Role of Rare Coding Variants in Parkinson's Disease GWAS Loci.

Introduction: Genome-wide association studies (GWAS) have identified multiple loci associated with Parkinson's disease (PD) risk. The presence of rare variants within these loci that may account for the increased susceptibility requires further investigation.Methods: Using exome sequencing, we performed a comprehensive rare variant screen of genes located within 56 novel PD loci. We first analyzed exomes from 109 subjects in the discovery cohort (85 diagnosed with PD and 24 healthy controls) and filtered for rare coding variants with minor allele frequency <0.01 and combined annotation-dependent depletion > 15. Further investigation of exome data from a replication cohort of 2,859 European patients with PD (International Parkinson's Disease Genomics Consortium) and 24,146 non-Finnish European controls from gnomAD were used for association testing of specific rare variants found in the discovery cohort.Results: Our genetic screening identified 54 potential disease-relevant variants in 71 genes in 109 subjects. Six out of 54 variants were found in two or more patients and were not observed in healthy controls: DNAH1 p.A3639T, STAB1 p.S1089G, ANK2 p.V3634D, ANK2 p.R3906W, SH3GL2 p.G276V, and NOD2 p.G908R. Replication in the International Parkinson's Disease Genomics Consortium (IPDGC) confirmed the association with PD risk for three out of the six identified variants (STAB1 p.S1089G, SH3GL2 p.G276V, and NOD2 p.G908R) (p < 10−3).Conclusion: Our study suggests that some of the associations identified in PD risk loci can be ascribed to rare variants with likely functional effects that modify PD risk.

No genetic evidence for involvement of alcohol dehydrogenase genes in risk for Parkinson's disease

Multiple genes have been implicated in Parkinson's disease (PD), including causal gene variants and risk variants typically identified using genome-wide association studies. Variants in the alcohol dehydrogenase genes ADH1C and ADH1B are among the genes that have been associated with PD, suggesting that this family of genes may be important in PD. As part of the International Parkinson's Disease Genomics Consortium's efforts to scrutinize previously reported risk factors for PD, we explored genetic variation in the alcohol dehydrogenase genes ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6, and ADH7 using imputed genome-wide association study data from 15,097 cases and 17,337 healthy controls. Rare-variant association tests and single-variant score tests did not show any statistically significant association of alcohol dehydrogenase genetic variation with the risk for PD.

SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease.

Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society.

Establishing the role of rare coding variants in known Parkinson's disease risk loci

Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks.

No clear support for a role for vitamin D in Parkinson's disease: A Mendelian randomization study.

Observational studies have found that relative to healthy controls, patients with Parkinson's disease have lower circulating concentrations of 25-hydroxyvitamin D, a clinical biomarker of vitamin D status. However, the causality of this association is uncertain. We undertook a Mendelian randomization study to investigate whether genetically decreased 25-hydroxyvitamin D concentrations are associated with PD to minimize confounding and prevent bias because of reverse causation. As instrumental variables for the Mendelian randomization analysis, we used 4 single-nucleotide polymorphisms that affect 25-hydroxyvitamin D concentrations (rs2282679 in GC, rs12785878 near DHCR7, rs10741657 near CYP2R1, and rs6013897 near CYP24A1). Summary effect size estimates of the 4 single-nucleotide polymorphisms on PD were obtained from the International Parkinson's Disease Genomics Consortium (including 5333 PD cases and 12,019 controls). The estimates of the 4 single-nucleotide polymorphisms were combined using an inverse-variance weighted meta-analysis. Of the 4 single-nucleotide polymorphisms associated with 25-hydroxyvitamin D concentrations, one (rs6013897 in CYP24A1) was associated with PD (odds ratio per 25-hydroxyvitamin D-decreasing allele, 1.09; 95% confidence interval, 1.02-1.16; P = 0.008), whereas no association was observed with the other 3 single-nucleotide polymorphisms (P > 0.23). The odds ratio of PD per genetically predicted 10% lower 25-hydroxyvitamin D concentration, based on the 4 single-nucleotide polymorphisms, was 0.98 (95% confidence interval, 0.93-1.04; P = 0.56). This Mendelian randomization study provides no clear support that lowered 25-hydroxyvitamin D concentration is causally associated with risk of PD. © 2017 International Parkinson and Movement Disorder Society.

Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data

SummaryBackgroundParkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2.MethodsWe used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients.FindingsWe included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0–55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5–61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005).InterpretationClinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both.FundingUK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, “Investissements d'Avenir” ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health.

Familial Aggregation of Panic Disturbances in Parkinson's Disease

Familial Aggregation of Panic Disturbances in Parkinson's Disease