Genetic risk factors in Finnish patients with Parkinson's disease

Introduction Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. Methods The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls. We screened for known genetic risk variants in GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT. In addition, DNA from 225 patients with early-onset Parkinson's disease was subjected to whole exome sequencing (WES). Results We detected a significant difference in the length variation of the CAG repeat in POLG1 between patients with early-onset PD compared to controls. The p.N370S and p.L444P variants in GBA contributed to a relative risk of 3.8 in early-onset PD and 2.5 in late-onset PD. WES revealed five variants in LRRK2 and SMPD1 that were found in the patients but not in the Finnish ExAC sequences. These are possible risk variants that require further confirmation. The p.G2019S variant in LRRK2, common in North African Arabs and Ashkenazi Jews, was not detected in any of the 849 PD patients. Conclusions The POLG1 CAG repeat length variation and the GBA p.L444P variant are associated with PD in the Finnish population.Peer reviewe

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

There is currently no disease-modifying treatment for Parkinson's disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative 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.Peer reviewe

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

There is currently no disease-modifying treatment for Parkinson's disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative 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.Peer reviewe

Finnish Parkinson's disease study integrating protein-protein interaction network data with exome sequencing analysis

Variants associated with Parkinson's disease (PD) have generally a small effect size and, therefore, large sample sizes or targeted analyses are required to detect significant associations in a whole exome sequencing (WES) study. Here, we used protein-protein interaction (PPI) information on 36 genes with established or suggested associations with PD to target the analysis of the WES data. We performed an association analysis on WES data from 439 Finnish PD subjects and 855 controls, and included a Finnish population cohort as the replication dataset with 60 PD subjects and 8214 controls. Single variant association (SVA) test in the discovery dataset yielded 11 candidate variants in seven genes, but the associations were not significant in the replication cohort after correction for multiple testing. Polygenic risk score using variants rs2230288 and rs2291312, however, was associated to PD with odds ratio of 2.7 (95% confidence interval 1.4-5.2; p < 2.56e-03). Furthermore, an analysis of the PPI network revealed enriched clusters of biological processes among established and candidate genes, and these functional networks were visualized in the study. We identified novel candidate variants for PD using a gene prioritization based on PPI information, and described why these variants may be involved in the pathogenesis of PD

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/

Genetics of Parkinson’s disease in Finland

Abstract Parkinson’s disease is the second most common neurodegenerative disease, affecting 1 % of the population at the age of 60 years in Finland. The latest studies estimate the heritablitity of PD to be around 27 %. Mendelian inheritance accounts for only a small proportion of PD and the majority of PD cases are thought to result from a complex mixture of risk factors. This is supported by the latest genome-wide association study (GWAS) meta-analysis that identified 90 risk loci, explaining 16–36 % of the heritability of PD. However, the majority of the variants underlying the loci, the pathomechanisms of PD and special characteristics of PD in Finland remain to be clarified. The present study investigated the genetics of PD, focusing especially on the Finnish population. We studied the role of the EIF4G1 gene in PD and identified a c.3513_3521del deletion preventing the translation of messenger-RNA in a Caucasian-American male. In a Finnish cohort, we did not find any significant association between variants in EIF4G1 and PD. We could not identify significant associations between established monogenic variants, risk variants and PD after correction for multiple testing. In GWAS single variant association (SVA) test, loci near genes GBA, SIPA1L2 and SNCA had almost significant associations to PD and the whole exome sequencing study (WES) identified a GBA variant rs2230288 with an altered allele frequency of 8.5 % in Finnish PD cases. Furthermore, the polygenic risk score (PRS) including variant rs2230288 in GBA and variant rs2291312 in TTN was associated with PD with an odds ratio (OR) of 2.7 (95% confidence interval 1.4–5.2; p &lt; 2.56e-03). We identified several novel candidate variants and genes. In gene-level association analysis; some of the identified candidates included GPR126 with an OR of 1.056 and MPHOSPH10 with an OR of 1.53. In the SVA test, the most notable candidate variants included variant rs41289829 in NMBR, variant rs146727650 in GPR126 and variants rs140835766 and rs72681440 in PABPC1. Finally, we studied also biological processes associated with the identified genes using gene-set enrichment analysis (GSEA). Statistically significant classes in GSEA included phosphate metabolism, phosphorylation and organonitrogen compound metabolism.Tiivistelmä Parkinsonin tauti (PT) on toiseksi yleisin hermostorappeumasairaus, jonka vallitsevuus Suomessa on noin 1 % yli 60-vuotiailla. Uusimmat kaksostutkimukset arvioivat PT:n perinnöllisyyden olevan noin 27%. Taudilla on harvinaisia monogeenisiä muotoja, mutta PT:n oletetaan olevan pääasiallisesti monitekijäinen tauti, jossa useiden riskitekijöiden yhteisvaikutus johtaa taudin puhkeamiseen. Viimeisin meta-analyysi genomin kattavista assosiaatiotutkimuksista (genome-wide association study; GWAS) tunnistaa 90 riskilokusta, jotka voisivat selittää 16–36% PT:n perinnöllisyydestä. Variantit riskilokusten taustalla, niihin liittyvät patomekanismit ja tuntemus PT:n mahdollisista geneettisistä erityispiirteistä suomalaisessa väestössä ovat pääosin selvittämättä. Väitöskirjatutkimuksessa selvitettiin PT:n genetiikkaa keskittyen erityisesti suomalaiseen väestöön. Tutkimme EIF4G1 geenin merkitystä PT:ssa ja löysimme yhdeltä amerikkalaiselta PT-potilaalta harvinaisen c.3513_3521del deleetion, joka estää lähetti-RNA:n translaation yhdessä 39:stä transkriptissa. Suomalaisessa kohortissa EIF4G1:n ja PT:n välillä ei ollut yhteyttä. Tunnettujen monogeenisten muotojen, riskivarianttien ja PT:n välille ei löytynyt yhteyttä monimuuttujakorjauksen jälkeen. GWAS tutkimuksessa lokukset geenien GBA, SIPA1L2 ja SNCA lähettyvillä olivat kuitenkin lähellä tilastollista merkitsevyyttä, ja eksomisekvensointiaineistossa (whole exome sequencing, WES) GBA:n variantin rs2230288 alleelifrekvenssi oli 8.5% potilailla ja 4.7% kontrolleilla. Lisäksi polygeeninen riskipisteytys (polygenic risk score, PRS) joka sisälsi GBA variantin rs2230288 ja TTN-geenin variantin rs2291312 oli yhteydessä PT:iin vetosuhteella 2.7 (95%:n luottamusväli 1.4–5.2; p &lt; 2.56e-03). Tutkimuksessa tunnistettiin myös useita uusia ehdokasvariantteja ja -geenejä. Geenitason assosiaatioista vahvimpia kandidaatteja olivat GPR126 tulosuhteella (OR) 1.056 sekä MPHOSPH10 tulosuhteella 1.53. Yksittäisvarianteista puolestaan vahvimpia kandidaatteja olivat NMBR variantti rs41289829, GPR126 variantti rs146727650, sekä PABPC1 variantit rs140835766 ja rs72681440. Tutkimuksessa etsittiin myös PT:iin yhteydessä olevia biologisia prosesseja geeniryhmien rikastusanalyysillä (gene-set enrichment analysis, GSEA). Mielenkiintoisimpia tilastollisesti merkittäviä prosesseja olivat fosfaattimetabolian, fosforylaation ja typpeä sisältävien orgaanisten yhdisteiden metabolia

Finnish Parkinson’s disease study integrating protein-protein interaction network data with exome sequencing analysis

Abstract Variants associated with Parkinson’s disease (PD) have generally a small effect size and, therefore, large sample sizes or targeted analyses are required to detect significant associations in a whole exome sequencing (WES) study. Here, we used protein-protein interaction (PPI) information on 36 genes with established or suggested associations with PD to target the analysis of the WES data. We performed an association analysis on WES data from 439 Finnish PD subjects and 855 controls, and included a Finnish population cohort as the replication dataset with 60 PD subjects and 8214 controls. Single variant association (SVA) test in the discovery dataset yielded 11 candidate variants in seven genes, but the associations were not significant in the replication cohort after correction for multiple testing. Polygenic risk score using variants rs2230288 and rs2291312, however, was associated to PD with odds ratio of 2.7 (95% confidence interval 1.4–5.2; p &lt; 2.56e-03). Furthermore, an analysis of the PPI network revealed enriched clusters of biological processes among established and candidate genes, and these functional networks were visualized in the study. We identified novel candidate variants for PD using a gene prioritization based on PPI information, and described why these variants may be involved in the pathogenesis of PD

Biallelic expansion in RFC1 as a rare cause of Parkinson’s disease

Abstract An intronic expansion (AAGGG)exp in the RFC1 gene has recently been shown to cause recessively inherited cerebellar ataxia, neuropathy, and vestibular areflexia syndrome and, furthermore, a few patients with ataxia and parkinsonism have been reported. We investigated 569 Finnish patients with medicated parkinsonism for RFC1 and found biallelic (AAGGG)exp in three non-consanguineous patients with clinically confirmed Parkinson’s disease without ataxia suggesting that RFC1-related disorders include Parkinson’s disease as well