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

Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD

Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment

Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability

Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types

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)

Gestión del conocimiento: perspectiva multidisciplinaria. Volumen 13

El libro “Gestión del Conocimiento. Perspectiva Multidisciplinaria”, Volumen 13 de la Colección Unión Global, es resultado de investigaciones. Los capítulos del libro, son resultados de investigaciones desarrolladas por sus autores. El libro es una publicación internacional, seriada, continua, arbitrada, de acceso abierto a todas las áreas del conocimiento, orientada a contribuir con procesos de gestión del conocimiento científico, tecnológico y humanístico. Con esta colección, se aspira contribuir con el cultivo, la comprensión, la recopilación y la apropiación social del conocimiento en cuanto a patrimonio intangible de la humanidad, con el propósito de hacer aportes con la transformación de las relaciones socioculturales que sustentan la construcción social de los saberes y su reconocimiento como bien público. El libro “Gestión del Conocimiento. Perspectiva Multidisciplinaria”, Volumen 13, de la Colección Unión Global, es resultado de investigaciones. Los capítulos del libro, son resultados de investigaciones desarrolladas por sus autores. El libro cuenta con el apoyo de los grupos de investigación: Universidad Sur del Lago “Jesús María Semprúm” (UNESUR) - Zulia – Venezuela; Universidad Politécnica Territorial de Falcón Alonso Gamero (UPTFAG) - Falcón – Venezuela; Universidad Politécnica Territorial de Mérida Kléber Ramírez (UPTM) - Mérida - Venezuela; Universidad Guanajuato (UG) - Campus Celaya - Salvatierra - Cuerpo Académico de Biodesarrollo y Bioeconomía en las Organizaciones y Políticas Públicas (CABBOPP) - Guanajuato – México; Centro de Altos Estudios de Venezuela (CEALEVE) - Zulia – Venezuela, Centro Integral de Formación Educativa Especializada del Sur (CIFE - SUR) - Zulia – Venezuela; Centro de Investigaciones Internacionales SAS (CEDINTER) - Antioquia – Colombia y diferentes grupos de investigación del ámbito nacional e internacional que hoy se unen para estrechar vínculos investigativos, para que sus aportes científicos formen parte de los libros que se publiquen en formatos digital e impreso

Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development

Current threats faced by Neotropical parrot populations

Psittaciformes (parrots, cockatoos) are among the most endangered birds, with 31% of Neotropical species under threat. The drivers of this situation appear to be manifold and mainly of anthropogenic origin. However, this assessment is based on the last extensive consultation about the conservation situation of parrots carried out in the 1990s. Given the rapid development of anthropogenic threats, updated data are needed to strategize conservation actions. Using a population approach, we addressed this need through a wide-ranging consultation involving biologists, wildlife managers, government agencies and non-governmental conservation organizations. We gathered up-to-date information on threats affecting 192 populations of 96 Neotropical parrot species across 21 countries. Moreover, we investigated associations among current threats and population trends. Many populations were affected by multiple threats. Agriculture, Capture for the Pet Trade, Logging, each of them affected > 55% of the populations, suggesting a higher degree of risk than previously thought. In contrast to previous studies at the species level, our study showed that the threat most closely associated with decreasing population trends is now Capture for the local Pet Trade. Other threats associated with decreasing populations include Small-holder Farming, Rural Population Pressure, Nest Destruction by Poachers, Agro-industry Grazing, Small-holder Grazing, and Capture for the international Pet Trade. Conservation actions have been implemented on < 20% of populations. Our results highlight the importance of a population-level approach in revealing the extent of threats to wild populations. It is critical to increase the scope of conservation actions to reduce the capture of wild parrots for pets.We would also like to thank the European Network on Invasive Parakeets (ParrotNet. Cost Actions: ES1304-240316-071371, ES1304-240316-071371), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET-PIP 112-201501-0598), Agencia Nacional de Promoción Científica y Tecnológica (FONCyT-PICT 2015-2281), and Brazilian National Council of Research (CNPq) for financial support

Current threats faced by Neotropical parrot populations

Made available in DSpace on 2018-12-11T16:49:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-10-01Consejo Nacional de Investigaciones Científicas y TécnicasAgencia Nacional de Promoción Científica y TecnológicaPsittaciformes (parrots, cockatoos) are among the most endangered birds, with 31% of Neotropical species under threat. The drivers of this situation appear to be manifold and mainly of anthropogenic origin. However, this assessment is based on the last extensive consultation about the conservation situation of parrots carried out in the 1990s. Given the rapid development of anthropogenic threats, updated data are needed to strategize conservation actions. Using a population approach, we addressed this need through a wide-ranging consultation involving biologists, wildlife managers, government agencies and non-governmental conservation organizations. We gathered up-to-date information on threats affecting 192 populations of 96 Neotropical parrot species across 21 countries. Moreover, we investigated associations among current threats and population trends. Many populations were affected by multiple threats. Agriculture, Capture for the Pet Trade, Logging, each of them affected > 55% of the populations, suggesting a higher degree of risk than previously thought. In contrast to previous studies at the species level, our study showed that the threat most closely associated with decreasing population trends is now Capture for the local Pet Trade. Other threats associated with decreasing populations include Small-holder Farming, Rural Population Pressure, Nest Destruction by Poachers, Agro-industry Grazing, Small-holder Grazing, and Capture for the international Pet Trade. Conservation actions have been implemented on < 20% of populations. Our results highlight the importance of a population-level approach in revealing the extent of threats to wild populations. It is critical to increase the scope of conservation actions to reduce the capture of wild parrots for pets.Instituto Multidisciplinario sobre Ecosistemas y Desarrollo Sustentable CONICET—Universidad Nacional del Centro de la Provincia de Buenos AiresJustus-Liebig-Universität Giessen Department of Animal Ecology and SystematicsTexas A&M University Schubot Exotic Bird Health Center Department of Veterinary Pathobiology College of Veterinary MedicineSociedade de Pesquisa em Vida Selvagem e Educação AmbientalUniversidade Federal de SergipePrograma Lapa Verde Centro Científico TropicalFacultad de Ciencias Naturales y Museo Universidad Nacional de La PlataArea de Conservación Pacífico Central ACOPAC Programa de Vida SilvestreWildlife Conservation SocietyAarhus UniversityGrupo de Ecología Conservación de Islas A.C. (GECI)University of California Department of Environment Science Policy & ManagementUniversidad Nacional Federico VillarrealUniversidade Federal de GoiásInstituto Venezolano de Investigaciones CientíficasProyecto Selva de Pino ParanáUnidos por las Guacamayas A. C.SELVA: Investigación para la conservación en el NeotrópicoInstituto Nacional de Tecnología AgropecuariaUniversity of BrasíliaUniversidade Federal da Paraíba Centro de Ciências Exatas e da NaturezaCentro Nacional de Pesquisa e Conservação de Aves Silvestres/ICMBioUniversidade Federal do Pará Instituto de Ciências BiológicasGuyra ParaguayUniversity of Colorado Department of Integrative BiologyThe World Parrot TrustBirdsCaribbeanFundacion del RioUniversitat de BarcelonaSociedad Conservacionista Audubon de VenezuelaUniversidad de Sancti Spíritus ¨José Martí Pérez¨Estación Biológica de Doñana CSICFundación Pro-BosqueCompañeros en Vuelo PIF-SVInstituto de Investigaciones Marinas y Costeras CONICET—Universidad Nacional de Mar del PlataUniversity of North Texas Biological SciencesOne Earth ConservationInstituto Espaço SilvestreUniversidade do Estado do AmazonasNational Aviary Conservation and Field ResearchUniversity of Cape TownBirdlife InternationalPaso PacíficoUniversidade de Passo FundoBiola UniversityMinisterio del Ambiente y los Recursos Naturales (MARENA)Universidad Michoacana de San Nicolas de HidalgoFundação Universidade Federal de Mato Grosso do SulAQUASISFundación Botánica y Zoológica de BarranquillaProvitaCIT Jujuy CONICET—UNJuFundación de Ciencias para el Estudio y la Conservación de la Biodiversidad (INCEBIO)UNESP Instituto de Biociências de BotucatuUniversidad Nacional Autónoma de México Estación Biología Chamela Instituto de BiologíaVinculación Interdisciplinaria para el Desarrollo Ambiental y lo SocialMesserli Research Institute University of Veterinary MedicineMuseo Noel Kempff MercadoGobierno Autónomo Departamental de Santa CruzUniversidad Autónoma de SinaloaMuseu de Zoologia da Universidade de Sao Paulo (MZUSP)University of Freiburg Evolutionary Biology and Animal EcologyMuseu de História Natural Capão da ImbuiaFundação Neotropica do BrasilCEMAVE: Centro Nacional de Pesquisa para a Conservação das Aves SilvestresCORBIDIAsociación Fauna ForeverUniversity of San Francisco Xavier de ChuquisacaUniversidad Nacional Autónoma de México Museo de Zoología Facultad de CienciasU.S. Fish and Wildlife Service Puerto Rican Parrot Recovery ProgramEcho Parrots and PeopleCátedra de Ecología General y Recursos Naturales Universidad Nacional Arturo JauretcheFundación para la Investigación y Conservación de los Loros en Bolivia (CLB)Instituto de Bio y Geociencias del NOA CONICETLaboratorio Nacional de Análisis y Síntesis Ecológica Universidad Nacional Autónoma de MéxicoDepto. de Estudios Ambientales Universidad Simón BolívarUNESP Instituto de Biociências de BotucatuConsejo Nacional de Investigaciones Científicas y Técnicas: CONICET-PIP 112-201501-0598Agencia Nacional de Promoción Científica y Tecnológica: FONCyT-PICT 2015-228