
Assessing the role of variations in dementia genes on the risk to develop LBD in GBA-mutation carriers
Investigators:
- Humanitas University (Milan, Italy): Stefano Duga, Letizia Straniero
- Parkinson Institute of Milan: Gianni Pezzoli, Anna Zecchinelli
- Policlinico Hospital (Milan, Italy): Alessio Di Fonzo
Introduction and rationale
Contact: Should you be interested, do not hesitate to liaise with Stefano Duga and Alessio Di Fonzo.
U1-splicing mutations in monogenic PD genes
- Soemedi, R. et al. Pathogenic variants that alter protein code often disrupt splicing. Nat. Genet. (2017). doi:10.1038/ng.3837
- Lim, K. H., Ferraris, L., Filloux, M. E., Raphael, B. J. & Fairbrother, W. G. Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes. Proc. Natl. Acad. Sci. 108, 11093–11098 (2011).
- La Cognata, V., D’Agata, V., Cavalcanti, F. & Cavallaro, S. Splicing: is there an alternative contribution to Parkinson’s disease? Neurogenetics 16, 245–263 (2015).
- Boussaad, I. et al. A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease. Sci. Transl. Med. 12, (2020).
LONG-PD
Investigators: Katerina Markopoulou
GEO-PD includes 20 sites from 14 countries and 4 continents who have committed to collect and share DNAs and clinical data longitudinally for 15 years, for 3,000 Parkinson's disease cases. If you wish to be involved in this project, please contact Katerina.
Investigators: Rejko Krüger, Patrick May
If you wish to find out more, then contact Rejko.
Projects
DBS Project Proposal
Aim 1: Identify participant sites with active DBS programs that can provide detailed phenotype and either genotype information or DNA for de-identified genotyping.
Aim 2: Identify genetic factors that contribute to disease progression and outcomes in DBS patients.
Aim 3: Determine the significance of phenotypic and genetic factors in the choice of candidates for DBS surgery.
To pursue these aims, we seek active participation of an international working group, willing to work towards data harmonization and collaborative pooled analyses, including genotyping/sequencing for which appropriate consent would need to be developed. This effort can be coordinated within the context of GP2.
More specifically both retrospective and prospective studies are proposed. In the retrospective study, a detailed phenotypic and genotypic characterization of patients who already have undergone DBS will be obtained from participating sites. The prospective study will include the longitudinal annual follow up of these established DBS cases as well as enroll new cases.
To facilitate this effort, a study protocol is presented for discussion. Potential participants are asked to complete a survey, included below, to provide details about the information able to be gathered at their sites.
Study protocol
For any new or established case, the following phenotypic information is desired:
Those who want to contribute to the project, please contact: M. Farrer and K. Markopoulou | |||
LRRK2 modifier projectInvestigators: Prof. Alexis Brice, Paris Brain Institute
The study focuses on the hypothesis that genetic modifiers may affect the LRRK2 G2019S penetrance and age at onset by modulating gene expression. Recently, Trinh et al. identified a tagging SNP (rs2421947) in DNM3 for which the alternative allele is associated with an earlier age at onset in Tunisian G2019S carriers1.
The aim of the present study is to elucidate the genetic contribution to age at onset variability by identifying the possible effect of additional modifiers in G2019S linked PD. The strategy we use to find out loci of interest includes genome-wide association analysis for unrelated G2019S carriers using age at onset as both a quantitative and a qualitative trait. We have already recruited 1292 of LRRK2 G2019S patients thanks to our collaborators and our local cohort from three different ethnical background.
Our preliminary findings from genome-wide association analysis did not show any significant association with the DNM3 locus. However, our exploratory analysis on the North African cohort (N = 492 samples) identified two suggestive SNPs (rs1762792, p value = 8.70 10-8; rs1360821 p value = 1.00 10-7) by GWAS on chromosome 13q31.3 using the age at onset as a quantitative trait. Furthermore, when age at onset was dichotomised by the median age at onset the two suggestive SNPs (rs1762792, p value = 1.20 10-7; rs1360821, p value = 2.00 10-7) were confirmed. We finally used Kaplan–Meier analyses to compare how age of PD onset varied with rs1762792 genotypes in all 276 G2019S carriers analysed. The CC homozygotes had a median age at onset of 47 years; CT heterozygotes had a median age at onset of 52 years; TT homozygotes had a median age at onset of 57 years. The median age at onset of LRRK2 parkinsonism in rs1762792 CC homozygotes was 10 years younger than that of TT homozygotes suggesting a protective role of the wild type allele. These promising results were replicated in our European cohort.
We now aim to reach increase the power of the study by collecting more LRRK2 G2019S patients (DNA samples or genotyping data) and extend our GWAS results. To detect genes whose expression is associated with the significant locus we will search for expression quantitative trait loci (e QTL).In order to identify additional but rare variants we plan to use WGS/WES in LRRK2 carriers, with extreme ages at onset. Again including a large number of cases would provide an opportunity for identifying and validating the role of rare variants. | |||
GCH-1 mutation and PDInvestigator: Beomseok (BJ) Jeon from Seoul National University Hospital Background: A mutation in the GTP cyclohydrolase 1 (GCH-1) gene is a cause of Dopa-responsive dystonia (DRD). Previous studies showed that the some family members of DRD with GCH-1 mutation have parkinsonism with decreased DAT binding which is an evidence of nigral degeneration. A large-scale meta-analysis of genome-wide association data identified GCH-1 as one of the risk loci of PD. These findings suggested that the GCH-1 mutation may be a risk factor for nigral degeneration causing PD. However, our group recently published a case of PD patient with GCH-1 mutation showing excellent clinical course.1 Serial follow-up of dopamine transporter imaging (FP-CIT PET) of the patient suggested that GCH-1 mutation may have unmasked the subclinical pathology, thus conferring excellent clinical course at least apparently. Hypothesis: The PD patients with GCH-1 mutation would present with earlier-onset, benign clinical course with later development of motor complications and cognitive decline, requiring low levodopa dose, and relatively milder decrease in DAT binding. The clinical features of 44 patients of PD with GCH-1 genetic variant (13 with DAT imaging) from previously published studies matched the hypothesis.1 However, the hypothesis requires further support with larger number of samples. Method: We would like to collect clinical information of PD patients with the GCH-1 mutation. We would like to collect the age of onset, type of GCH-1 mutation, disease duration, Hoehn and Yahr stage, motor complications and cognitive decline, levodopa equivalent dose and dopamine transporter imaging. The detailed form is summarized in the attached case report form. *The information does not have to be complete. Analysis: We will summarize the clinical features of PD patients with GCH-1 mutation and see if they match with our hypothesis. Perspective: This study will support the hypothesis that GCH-1 mutation is not the cause of nigral degeneration but unmasks subclinical pathology. |