Comprehensive Unbiased Risk factor Assessment for Genetics and Environment in Parkinson's Disease
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Despite the advances in the identification of genes involved in Parkinson's disease (PD), there are still appreciable gaps in our understanding of PD. Therefore we propose a comprehensive approach based on (i) a unique collection of families and (ii) large cohorts of sporadic PD patients for (iii) genetic studies and (iv) assessment of environmental modifiers that will translate into (v) functional validation studies.
Using NGS strategies, we will disentangle the complex genetic architecture of PD and better define the underlying functional variants in disease-associated GWAS loci. Newly identified genetic variants are filtered for pathogenic relevance and replicated in large cohorts of PD patients also using the unique resources of the GEO-PD Consortium. Subsequent assessment of disease modifiers includes two complementary approaches: Mendelian randomization, and gene-environment interaction studies. To validate genetic risk variants, functional studies on patient biomaterial will be performed based on (i) the unique expertise for fibroblasts- and iPSC-derived cellular models of PD and (ii) a large repository of biomaterials from carriers of PD-associated mutations. Established readouts allow to study functional effects of identified genetic risk factors and will be used to assign novel disease genes and risk variants to defined pathogenic pathways. Moreover patient-based cellular models will be challenged with environmental risk factors identified as modulators of disease.
Using NGS strategies, we will disentangle the complex genetic architecture of PD and better define the underlying functional variants in disease-associated GWAS loci. Newly identified genetic variants are filtered for pathogenic relevance and replicated in large cohorts of PD patients also using the unique resources of the GEO-PD Consortium. Subsequent assessment of disease modifiers includes two complementary approaches: Mendelian randomization, and gene-environment interaction studies. To validate genetic risk variants, functional studies on patient biomaterial will be performed based on (i) the unique expertise for fibroblasts- and iPSC-derived cellular models of PD and (ii) a large repository of biomaterials from carriers of PD-associated mutations. Established readouts allow to study functional effects of identified genetic risk factors and will be used to assign novel disease genes and risk variants to defined pathogenic pathways. Moreover patient-based cellular models will be challenged with environmental risk factors identified as modulators of disease.
Organisations
Publications
Blauwendraat C
(2018)
Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease.
in JAMA neurology
Blauwendraat C
(2017)
NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases.
in Neurobiology of aging
Bodea CA
(2016)
A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies.
in American journal of human genetics
Boot E
(2018)
Typical features of Parkinson disease and diagnostic challenges with microdeletion 22q11.2.
in Neurology
Brainstorm Consortium
(2018)
Analysis of shared heritability in common disorders of the brain.
in Science (New York, N.Y.)
Charlesworth G
(2015)
Mutations in HPCA cause autosomal-recessive primary isolated dystonia.
in American journal of human genetics
Escott-Price V
(2015)
Polygenic risk of Parkinson disease is correlated with disease age at onset.
in Annals of neurology
Ferrari R
(2018)
Stratification of candidate genes for Parkinson's disease using weighted protein-protein interaction network analysis.
in BMC genomics
Jansen IE
(2017)
Establishing the role of rare coding variants in known Parkinson's disease risk loci.
in Neurobiology of aging
Kia DA
(2018)
Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson's disease.
in Annals of neurology
Title | Research data capture |
Description | Database framework for recruitment and for entering study data via electronic forms, including directly from participants, |
Type Of Material | Database/Collection of data |
Year Produced | 2012 |
Provided To Others? | Yes |
Impact | Consolidation of research studies, common data model deployed across internal and external groups, improved data capture and study management, use UCLH hospital setting. |