Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Non-dopaminergic symptoms in Parkinson’s disease

Parkinson’s disease (PD) is well known for the dopaminergic symptoms: tremor, rigidity and bradykinesia. PD patients can also suffer from various non-dopaminergic symptoms like: postural instability, cognitive dysfunction and autonomic symptoms. The impact of these non-dopaminergic symptoms on overall disease burden and prognosis is not well known. In addition proper research on diagnosis and treatment of specific non-dopaminergic symptoms is lacking. In this thesis we show that prognosis in PD in terms of disability is mainly determined by the early presence of non-dopaminergic symptoms. In addition we present a prognostic model which allows individual patient prognostication with variables that can easily be obtained at the moment of diagnosis. In this thesis we also focus on one specific part of the autonomic symptoms in PD: orthostatic hypotension (OH). We show that a substantial proportion of PD patients have OH, but that the scientific literature concerning this symptom is biased by studies performed in tertiary care populations. In addition, we show that the results of orthostatic blood pressure measurements have no clear association with the orthostatic symptoms that PD patients experience in daily life. Additional autonomic function tests show a better association with daily experienced orthostatic symptoms, but these tests are difficult to perform and their test characteristics remained relatively poor. The search for better diagnostic tests for this specific problem needs to continue

Prevalence of orthostatic hypotension in Parkinson's disease: a systematic review and meta-analysis

Although orthostatic hypotension (OH) is recognized as one of the main non-motor symptoms of Parkinson's disease (PD), there is inconsistent evidence about the prevalence of OH in PD. To estimate the prevalence of OH in PD more precisely we conducted a systematic review of the literature. From PubMed and Embase searches with predefined inclusion criteria, we identified studies published up till December 2009. Prevalence numbers from studies were pooled using a non-linear random-effects meta-analysis. We found 25 studies from which the prevalence of OH could be calculated. The pooled estimate of the point prevalence of OH in PD was 30.1% (95% CI: 22.9% to 38.4%). We found a large statistical heterogeneity between studies which could not be reduced by several subgroup analyses. The estimated prevalence of OH in PD is 30%. However, due to the large heterogeneity between studies this pooled estimate should be interpreted with caution. More data from unselected population-based cohorts are neede

Incidence and characteristics of chronic and lymphoplasmacytic sclerosing pancreatitis in patients scheduled to undergo a pancreatoduodenectomy

AbstractBackgroundThe determination of the exact nature of a pancreatic head mass in a patient scheduled to undergo a pancreatoduodenectomy can be very difficult. This is important as patients who suffer from benign disease such as pancreatitis do not always require surgery. The aim of the present study was to analyse the incidence of pancreatitis and the signs and symptoms associated with these tumours mistaken for pancreatic cancer and the diagnostic procedures performed.MethodsA consecutive group of patients who underwent a pancreatoduodenectomy between 1992 and 2005 with histopathologically proven pancreatic adenocarcinoma (PCA) and pancreatitis were analysed.ResultsThe incidence of pancreatitis after pancreatoduodenectomy is 63 out of 639 patients who underwent a pancreaticoduodenectomy (9.9%). Of these patients, 24 patients (38%) had lymphoplasmacytic sclerosing pancreatitis (LPSP) and 31 patients (49%) had focal chronic pancreatitis. Eight patients (13%) had an intermediate form with characteristics of both. Pancreatic adenocarcinoma occurred in 227 patients (36%). The presence of pancreatitis without a discrete mass on endoscopic ultrasonography (EUS) seemed to have clinical relevance with a positive likelihood ratio of 5.1. Mortality after resection was nil in both groups.ConclusionThe incidence of pancreatitis is 9.9% for patients scheduled to undergo a pancreatoduodenectomy. Of these patients, 38% had LPSP, 13% had a intermediate form and 49% had focal chronic pancreatitis. The determination of the exact nature of a pancreatic head mass remains difficult

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

International audienceAutosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson disease (PD), and common variants around LRRK2 are a risk factor for sporadic PD. Using protein-protein interaction arrays, we identified BCL2-associated athanogene 5, Rab7L1 (RAB7, member RAS oncogene family-like 1), and Cyclin-G-associated kinase as binding partners of LRRK2. The latter two genes are candidate genes for risk for sporadic PD identified by genome-wide association studies. These proteins form a complex that promotes clearance of Golgi-derived vesicles through the autophagy-lysosome system both in vitro and in vivo. We propose that three different genes for PD have a common biological function. More generally, data integration from multiple unbiased screens can provide insight into human disease mechanism

Genetic comorbidities in Parkinson's disease

Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain

Use of support vector machines for disease risk prediction in genome-wide association studies: Concerns and opportunities

The success of genome-wide association studies (GWAS) in deciphering the genetic architecture of complex diseases has fueled the expectations whether the individual risk can also be quantified based on the genetic architecture. So far, disease risk prediction based on top-validated single-nucleotide polymorphisms (SNPs) showed little predictive value. Here, we applied a support vector machine (SVM) to Parkinson disease (PD) and type 1 diabetes (T1D), to show that apart from magnitude of effect size of risk variants, heritability of the disease also plays an important role in disease risk prediction. Furthermore, we performed a simulation study to show the role of uncommon (frequency 1-5%) as well as rare variants (frequency <1%) in disease etiology of complex diseases. Using a cross-validation model, we were able to achieve predictions with an area under the receiver operating characteristic curve (AUC) of ~0.88 for T1D, highlighting the strong heritable component (∼90%). This is in contrast to PD, where we were unable to achieve a satisfactory prediction (AUC ~0.56; heritability ~38%). Our simulations showed that simultaneous inclusion of uncommon and rare variants in GWAS would eventually lead to feasible disease risk prediction for complex diseases such as PD. The used software is available at http://www.ra.cs.uni-tuebingen.de/software/MACLEAPS/

Genome-wide association study confirms extant PD risk loci among the Dutch

In view of the population-specific heterogeneity in reported genetic risk factors for Parkinson's disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514 799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P=1.63 × 10−5, OR=1.325 and BST1, rs12502586: P=1.63 × 10−3, OR=1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3′ and 5′ ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P=1.22 × 10−4, OR=1.51; HLA, rs4248166: P=4.39 × 10−5, OR=1.36; and MAPT, rs3785880: P=1.9 × 10−3, OR=1.19)