Genome-wide determinants of mortality and motor progression in Parkinson's disease.

There are 90 independent genome-wide significant genetic risk variants for Parkinson's disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.

Lysosomal Polygenic Burden Drives Cognitive Decline in Parkinson's Disease with Low Alzheimer Risk.

BACKGROUND: Genetics influence cognitive progression in Parkinson's disease, possibly through mechanisms related to Lewy and Alzheimer's disease pathology. Lysosomal polygenic burden has recently been linked to more severe Lewy pathology post mortem. OBJECTIVES: To assess the influence of lysosomal polygenic burden on cognitive progression in Parkinson's disease patients with low Alzheimer's disease risk. METHODS: Using Cox regression we assessed association between lysosomal polygenic scores and time to Montreal Cognitive Assessment score ≤ 21 in the Parkinson's Progression Markers Initiative cohort (n = 374), with replication in data from the Parkinson's Disease Biomarker Program (n = 777). Patients were stratified by Alzheimer's disease polygenic risk. RESULTS: The lysosomal polygenic score was associated with faster progression of cognitive decline in patients with low Alzheimer's disease risk in both datasets (P = 0.0032 and P = 0.0054, respectively). CONCLUSION: Our study supports complex interplay between genetics and neuropathology in Parkinson's disease-related cognitive impairment, emphasizing the role of lysosomal polygenic burden. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2).

The Global Parkinson's Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia.

Genetic meta-analysis of levodopa induced dyskinesia in Parkinson's disease.

The genetic basis of levodopa-induced-dyskinesia (LiD) is poorly understood, and there have been few well-powered genome-wide studies. We performed a genome-wide survival meta-analyses to study the effect of genetic variation on the development of LiD in five separate longitudinal cohorts, and meta-analysed the results. We included 2784 PD patients, of whom 14.6% developed LiD. We found female sex (HR = 1.35, SE = 0.11, P = 0.007) and younger age at onset (HR = 1.8, SE = 0.14, P = 2 × 10-5) increased the probability of developing LiD. We identified three genetic loci significantly associated with time-to-LiD onset. rs72673189 on chromosome 1 (HR = 2.77, SE = 0.18, P = 1.53 × 10-8) located at the LRP8 locus, rs189093213 on chromosome 4 (HR = 3.06, SE = 0.19, P = 2.81 × 10-9) in the non-coding RNA LINC02353 locus, and rs180924818 on chromosome 16 (HR = 3.13, SE = 0.20, P = 6.27 × 10-9) in the XYLT1 locus. Based on a functional annotation analysis on chromosome 1, we determined that changes in DNAJB4 gene expression, close to LRP8, are an additional potential cause of increased susceptibility to LiD. Baseline anxiety status was significantly associated with LiD (OR = 1.14, SE = 0.03, P = 7.4 × 10-5). Finally, we performed a candidate variant analysis of previously reported loci, and found that genetic variability in ANKK1 (rs1800497, HR = 1.27, SE = 0.09, P = 8.89 × 10-3) and BDNF (rs6265, HR = 1.21, SE = 0.10, P = 4.95 × 10-2) loci were significantly associated with time to LiD in our large meta-analysis.

Genetic meta-analysis of levodopa induced dyskinesia in Parkinson's disease.

Importance: Forty percent of Parkinson's disease patients develop levodopa-induced-dyskinesia (LiD) within 4 years of starting levodopa. The genetic basis of LiD remains poorly understood, and there have been few well powered studies. Objective: To discover common genetic variants in the PD population that increase the probability of developing LiD. Design setting and Participants: We performed survival analyses to study the development of LiD in 5 separate longitudinal cohorts. We performed a meta-analysis to combine the results of genetic association from each study based on a fixed effects model weighting the effect sizes by the inverse of their standard error. The selection criteria was specific to each cohort. We studied individuals that were genotyped from each cohort and that passed our analysis specific inclusion criteria. Main Outcomes and Measures: We measured the time for PD patients on levodopa treatment to develop LiD as defined by reaching a score higher or equal than 2 from the MDS-UPDRS part IV, item 1, which is equivalent to a range of 26%-50% of the waking time with dyskinesia. We carried out a genome-wide analysis of the hazard ratio and the association of genome-wide SNPs with the probability of developing LiD using cox proportional hazard models (CPH). Results: This study included 2,784 PD patients of European ancestry, of whom 14.6% developed LiD. Consistent with previous studies, we found female gender (HR = 1.35, SE = 0.11, P = 0.007) and younger age at onset (HR = 1.8, SE = 0.14, P = 2 × 10 -5 ) to increase the probability of developing LiD. We identified three loci significantly associated with time-to-LiD onset. rs72673189 on chromosome 1 (HR = 2.77, SE = 0.18, P = 1.53 × 10 -8 ) located in the LRP8 locus, rs189093213 on chromosome 4 (HR = 3.06,, SE = 0.19, P = 2.81 × 10 -9 ) in the non-coding RNA LINC02353 locus, and rs180924818 on chromosome 16 (HR = 3.13, SE = 0.20, P = 6.27 × 10 -9 ) in the XYLT1 locus. Subsequent colocalization analyses on chromosome 1 identified DNAJB4 as a candidate gene associated with LiD through a change in gene expression. We computed a PRS based on our GWAS meta-analysis and found high accuracy to stratify between PD-LID and PD (AUC 83.9). We also performed a stepwise regression analysis for baseline features selection associated with LiD status. We found baseline anxiety status to be significantly associated with LiD (OR = 1.14, SE = 0.03, P = 7.4 × 10 -5 ). Finally, we performed a candidate variant analysis and found that genetic variability in ANKK1 ( rs1800497 , Beta = 0.24, SE = 0.09, P = 8.89 × 10 -3 ) and BDNF ( rs6265 , Beta = 0.19, SE = 0.10, P = 4.95 × 10 -2 ) loci were significantly associated with time to LiD in our large meta-analysis. Conclusion: In this association study, we have found three novel genetic variants associated with LiD, as well as confirming reports that variability in ANKK1 and BDNF loci were significantly associated with LiD probability. A PRS nominated from our time-to-LiD meta-analysis significantly differentiated between PD-LiD and PD. In addition, we have found female gender, young PD onset and anxiety to be significantly associated with LiD.

Lysosomal polygenic risk is associated with the severity of neuropathology in Lewy body disease.

Intraneuronal accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson's disease and dementia with Lewy bodies, often co-occurring with variable degrees of Alzheimer's disease related neuropathology. Genetic association studies have successfully identified common variants associated with disease risk and phenotypic traits in Lewy body disease, yet little is known about the genetic contribution to neuropathological heterogeneity. Using summary statistics from Parkinson's disease and Alzheimer's disease genome-wide association studies, we calculated polygenic risk scores and investigated the relationship with Lewy, amyloid-ß and tau pathology. Associations were nominated in neuropathologically defined samples with Lewy body disease from the Netherlands Brain Bank (n = 217) and followed up in an independent sample series from the Mayo Clinic Brain Bank (n = 394). We also generated stratified polygenic risk scores based on single-nucleotide polymorphisms annotated to eight functional pathways or cell types previously implicated in Parkinson's disease and assessed for association with Lewy pathology in subgroups with and without significant Alzheimer's disease co-pathology. In an ordinal logistic regression model, the Alzheimer's disease polygenic risk score was associated with concomitant amyloid-ß and tau pathology in both cohorts. Moreover, both cohorts showed a significant association between lysosomal pathway polygenic risk and Lewy pathology, which was more consistent than the association with a general Parkinson's disease risk score and specific to the subset of samples without significant concomitant Alzheimer's disease related neuropathology. Our findings provide proof of principle that the specific risk alleles a patient carries for Parkinson's and Alzheimer's disease also influence key aspects of the underlying neuropathology in Lewy body disease. The interrelations between genetic architecture and neuropathology are complex, as our results implicate lysosomal risk loci specifically in the subset of samples without Alzheimer's disease co-pathology. Our findings hold promise that genetic profiling may help predict the vulnerability to specific neuropathologies in Lewy body disease, with potential relevance for the further development of precision medicine in these disorders.

The IPDGC/GP2 Hackathon - an open science event for training in data science, genomics, and collaboration using Parkinson's disease data.

Open science and collaboration are necessary to facilitate the advancement of Parkinson's disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities, thus we coordinated a virtual 3-day hackathon event, during which 49 early-career scientists from 12 countries built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. Each team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. Hackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early-career researchers. The resources generated can be used to accelerate research on the genetics of PD.

Association between the LRP1B and APOE loci and the development of Parkinson's disease dementia.

Parkinson's disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson's disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson's disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson's disease dementia, we performed a genome-wide survival meta-analysis of 3923 clinically diagnosed Parkinson's disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of individuals with Parkinson's disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson's disease dementia [hazard ratio = 2.41 (1.94-3.00), P = 2.32 × 10-15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazard ratio = 3.23 (2.17-4.81), P = 7.07 × 10-09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazard ratio = 2.02 (1.21-3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson's disease dementia, with significantly reduced levels of amyloid ß42 (P = 0.0012) in Parkinson's disease dementia compared to Parkinson's disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson's disease dementia.

Sequence of clinical and neurodegeneration events in Parkinson's disease progression.

Dementia is one of the most debilitating aspects of Parkinson's disease. There are no validated biomarkers that can track Parkinson's disease progression, nor accurately identify patients who will develop dementia and when. Understanding the sequence of observable changes in Parkinson's disease in people at elevated risk for developing dementia could provide an integrated biomarker for identifying and managing individuals who will develop Parkinson's dementia. We aimed to estimate the sequence of clinical and neurodegeneration events, and variability in this sequence, using data-driven statistical modelling in two separate Parkinson's cohorts, focusing on patients at elevated risk for dementia due to their age at symptom onset. We updated a novel version of an event-based model that has only recently been extended to cope naturally with clinical data, enabling its application in Parkinson's disease for the first time. The observational cohorts included healthy control subjects and patients with Parkinson's disease, of whom those diagnosed at age 65 or older were classified as having high risk of dementia. The model estimates that Parkinson's progression in patients at elevated risk for dementia starts with classic prodromal features of Parkinson's disease (olfaction, sleep), followed by early deficits in visual cognition and increased brain iron content, followed later by a less certain ordering of neurodegeneration in the substantia nigra and cortex, neuropsychological cognitive deficits, retinal thinning in dopamine layers, and further deficits in visual cognition. Importantly, we also characterize variation in the sequence. We found consistent, cross-validated results within cohorts, and agreement between cohorts on the subset of features available in both cohorts. Our sequencing results add powerful support to the increasing body of evidence suggesting that visual processing specifically is affected early in patients with Parkinson's disease at elevated risk of dementia. This opens a route to earlier and more precise detection, as well as a more detailed understanding of the pathological mechanisms underpinning Parkinson's dementia.

Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study.

BACKGROUND: The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP). METHODS: In stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets. FINDINGS: Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead single nucleotide polymorphism rs2242367, p=7·5 × 10-10, hazard ratio 1·42 [95% CI 1·22-1·67]). rs2242367 was associated with survival in the individuals added in stage two (n=238; p=0·049, 1·22 [1·00-1·48]) and in the pooled analysis of both stages (n=1239; p=1·3 × 10-10, 1·37 [1·25-1·51]). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs), LINC02555 and AC079630.4, in whole blood. Although we did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed a posterior probability of hypothesis 4 of 0·77, suggesting colocalisation due to a single shared causal variant. INTERPRETATION: Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association might be through a lncRNA-regulated effect on LRRK2 expression because LINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 has been associated with sporadic and familial forms of Parkinson's disease, and our finding suggests a genetic overlap with PSP. Further functional studies will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP and related tauopathies. FUNDING: PSP Association, CBD Solutions, Medical Research Council (UK).

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk.

Genome-Wide Association Studies of Cognitive and Motor Progression in Parkinson's Disease.

BACKGROUND: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies have identified variants associated with disease risk, but not progression. The objective of the current study was to identify genetic variants associated with PD progression. METHODS: We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, in which we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analyzed in linear regression in genome-wide association studies. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis. RESULTS: There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE ε4 tagging variant, rs429358, was significantly associated with composite and cognitive progression in PD. Conditional analysis revealed several independent signals in the APOE locus for cognitive progression. No single variants were associated with motor progression. However, in gene-based analysis, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (P = 5.3 × 10-6 ). CONCLUSIONS: We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE ε4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome.

Importance: Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied. Objective: To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD. Design, Setting, Participants: This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019. Main Outcomes and Measures: Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures. Results: A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05). Conclusions and Relevance: These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.

Genetic analysis of Mendelian mutations in a large UK population-based Parkinson's disease study.

Our objective was to define the prevalence and clinical features of genetic Parkinson's disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson's Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson's study, 424 had young-onset Parkinson's disease (age at onset ≤ 50) and 1799 had late onset Parkinson's disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 'Kompetitive' allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson's disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson's disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.

The genetic and clinico-pathological profile of early-onset progressive supranuclear palsy.

BACKGROUND: Studies on early-onset presentations of progressive supranuclear palsy (PSP) have been limited to those where a rare monogenic cause has been identified. Here, we have defined early-onset PSP (EOPSP) and investigated its genetic and clinico-pathological profile in comparison with late-onset PSP (LOPSP) and Parkinson's disease (PD). METHODS: We included subjects from the Queen Square Brain Bank, PROSPECT-UK study, and Tracking Parkinson's study. Group comparisons of data were made using Welch's t-test and Kruskal-Wallis analysis of variance. EOPSP was defined as the youngest decile of motor age at onset (≤55 years) in the Queen Square Brain Bank PSP case series. RESULTS: We identified 33 EOPSP, 328 LOPSP, and 2000 PD subjects. The early clinical features of EOPSP usually involve limb parkinsonism and gait freezing, with 50% of cases initially misdiagnosed as having PD. We found that an initial clinical diagnosis of EOPSP had lower diagnostic sensitivity (33%) and positive predictive value (38%) in comparison with LOPSP (80% and 76%) using a postmortem diagnosis of PSP as the gold standard. 3/33 (9%) of the EOPSP group had an underlying monogenic cause. Using a PSP genetic risk score (GRS), we showed that the genetic risk burden in the EOPSP (mean z-score, 0.59) and LOPSP (mean z-score, 0.48) groups was significantly higher (P < 0.05) when compared with the PD group (mean z-score, -0.08). CONCLUSIONS: The initial clinical profile of EOPSP is often PD-like. At the group level, a PSP GRS was able to differentiate EOPSP from PD, and this may be helpful in future diagnostic algorithms. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype.

OBJECTIVE: The basis for clinical variation related to underlying progressive supranuclear palsy (PSP) pathology is unknown. We performed a genome-wide association study (GWAS) to identify genetic determinants of PSP phenotype. METHODS: Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson syndrome (RS) and non-RS groups. We carried out separate logistic regression GWASs to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS = 367, non-RS = 130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/coexpression patterns of our identified genes and used our data to carry out gene-based association testing. RESULTS: Our lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome-wide significance in our whole cohort analysis (odds ratio = 5.5, 95% confidence interval = 3.2-10.0, p = 1.7 × 10-9 ). rs564309 is an intronic variant of the tripartite motif-containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene-based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia. INTERPRETATION: Our study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease-modifying therapies. Ann Neurol 2018;84:485-496.