Additional rare variant analysis in Parkinson's Disease cases with and without known pathogenic mutations: evidence for oligogenic inheritance

Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson’s (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognized primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of no known mutation PD cases harbor a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of PD patients and their families

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

BACKGROUND: Parkinson'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. METHODS: We 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. FINDINGS: We 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). INTERPRETATION: Clinicians 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. FUNDING: UK 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.UK 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.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/S1474-4422(16)00071-

Differences in the Presentation and Progression of Parkinson's Disease by Sex.

BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society.This study was supported by the Intramural Research Program the National Institute on Aging (NIA, Z01-AG000949-02), Biogen Idec, and the Michael J Fox Foundation for Parkinson’s Research

Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts.

OBJECTIVE: To determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression. METHODS: We evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed. RESULTS: We confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69-6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04-20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16-1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19-2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (-0.72 [-1.21 to -0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27-1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21-1.03]). CONCLUSIONS: This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.The Intramural Research Program the National Institute on Aging (NIA, Z01-AG000949-02), Biogen Idec, and the Michael J Fox Foundation for Parkinson’s Researc

ADAMS project: a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the UK

PURPOSE: Genetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of these findings. The genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis (ADAMS) project aims to gather genetic and phenotypic data on a large cohort of ancestrally-diverse individuals with MS living in the UK. PARTICIPANTS: Adults with self-reported MS from diverse ancestral backgrounds. Recruitment is via clinical sites, online (https://app.mantal.co.uk/adams) or the UK MS Register. We are collecting demographic and phenotypic data using a baseline questionnaire and subsequent healthcare record linkage. We are collecting DNA from participants using saliva kits (Oragene-600) and genotyping using the Illumina Global Screening Array V.3. FINDINGS TO DATE: As of 3 January 2023, we have recruited 682 participants (n=446 online, n=55 via sites, n=181 via the UK MS Register). Of this initial cohort, 71.2% of participants are female, with a median age of 44.9 years at recruitment. Over 60% of the cohort are non-white British, with 23.5% identifying as Asian or Asian British, 16.2% as Black, African, Caribbean or Black British and 20.9% identifying as having mixed or other backgrounds. The median age at first symptom is 28 years, and median age at diagnosis is 32 years. 76.8% have relapsing-remitting MS, and 13.5% have secondary progressive MS. FUTURE PLANS: Recruitment will continue over the next 10 years. Genotyping and genetic data quality control are ongoing. Within the next 3 years, we aim to perform initial genetic analyses of susceptibility and severity with a view to replicating the findings from European-ancestry studies. In the long term, genetic data will be combined with other datasets to further cross-ancestry genetic discoveries

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

Identification of candidate Parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations