NGFN-PLUS
Genomics of Parkinson’s Disease
| Coordinator: | Prof. Dr. Thomas Gasser | |
| Institution: | Hertie-Institut für klinische Hirnforschung | |
| Homepage: | www.hih-tuebingen.de/nd/ |
For the analysis of genomics of PD we expand our previous work to generate a comprehensive model of PD pathogenesis.
The specific aims of the current project are:
(1) Identification of novel genes and loci through genome-wide association study (GWAS)
GWAS with PD phenotypes are predicted to generate a number of candidate loci causative for PD. Candidates will be analysed in expanded samples of patients and different strategies will be applied to prioritise candidate genes for detailed investigations. For replication of the most significant single nucleotide polymorphisms (SNPs), the most significant variant in a gene that could be involved in the onset of PD, we will use cohorts available in this IG and those of international collaborators.
(2) Expansion of existing networks of genes and loci
Building on our previous characterization of several genes and loci and on information derived from the numerous models systems and screening projects of this IG, we will expand existing networks of candidate genes and loci. We will especially follow up on our two major findings, the LRRK2 mutations and the PD associated α-synuclein haplotypes, as α-synuclein expression appears to be an essential factor in PD pathogenesis.
(3) Functional consequences of identified variants in vitro and in vivo
We have established a biobank containing DNA, cerebrospinal fluid (CSF), peripheral blood mononuclear cells (PBMCs), fibroblasts, and serum from patients with PD and controls. Functional consequences of genetic variants, identified in this subproject, will be analyzed in vitro for example by expression studies in patient-derived cells and body fluids. The findings will be made available for validation in cellular and animal models of the IG. Eventually the results will help us to stratify patients according to specific genetic risk profiles, which will be an important prerequisite for successful clinical disease modifying trials.
(4) Validation of genetic data in big prospective studies
Genetic findings will be prospectively validated in a cohort of at least 1800 healthy elderly, phenotyped for premotor signs of PD. This unique cohort will for the first time allow to prospectively study genetic risk factors. Associations of appearance of premotor signs with genetic variants will be determined and occurrence of additional premotor signs and conversion rates to PD will be used as an outcome measure.
The specific aims of the current project are:
(1) Identification of novel genes and loci through genome-wide association study (GWAS)
GWAS with PD phenotypes are predicted to generate a number of candidate loci causative for PD. Candidates will be analysed in expanded samples of patients and different strategies will be applied to prioritise candidate genes for detailed investigations. For replication of the most significant single nucleotide polymorphisms (SNPs), the most significant variant in a gene that could be involved in the onset of PD, we will use cohorts available in this IG and those of international collaborators.
(2) Expansion of existing networks of genes and loci
Building on our previous characterization of several genes and loci and on information derived from the numerous models systems and screening projects of this IG, we will expand existing networks of candidate genes and loci. We will especially follow up on our two major findings, the LRRK2 mutations and the PD associated α-synuclein haplotypes, as α-synuclein expression appears to be an essential factor in PD pathogenesis.
(3) Functional consequences of identified variants in vitro and in vivo
We have established a biobank containing DNA, cerebrospinal fluid (CSF), peripheral blood mononuclear cells (PBMCs), fibroblasts, and serum from patients with PD and controls. Functional consequences of genetic variants, identified in this subproject, will be analyzed in vitro for example by expression studies in patient-derived cells and body fluids. The findings will be made available for validation in cellular and animal models of the IG. Eventually the results will help us to stratify patients according to specific genetic risk profiles, which will be an important prerequisite for successful clinical disease modifying trials.
(4) Validation of genetic data in big prospective studies
Genetic findings will be prospectively validated in a cohort of at least 1800 healthy elderly, phenotyped for premotor signs of PD. This unique cohort will for the first time allow to prospectively study genetic risk factors. Associations of appearance of premotor signs with genetic variants will be determined and occurrence of additional premotor signs and conversion rates to PD will be used as an outcome measure.
KTT
MEDIA
CURRENT
NGFN-MEETING-2012
NGFN- MEETING
NGFN1&2
LINKS