Welcome to the AD/PD™ 2022 Interactive Program
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IDENTIFICATION OF GENETIC VARIATION AND TRANSCRIPTIONAL PERTURBATIONS IMPLICATED IN PARKINSON’S DISEASE
Abstract
Aims
This study aims to systematically characterize and functionally annotate the candidate structural variants (SVs) causal for Parkinson's disease (PD) using dopaminergic neuronal (DN) cell cultures derived from healthy controls and idiopathic (iPD) patients iPSC lines.
Methods
For this purpose, we generated long-read DNA and RNA sequencing data from 10 DN cell lines with ONT-PromethION. Long-read DNA sequencing data was used for SV detection. Long-read RNA-seq data was used for isoform expression and splicing analysis. Resolved perturbations in the transcriptome were associated to the presence of SVs in the coding and non-coding regions.
Results
We developed a conceptual approach for SV prioritization on genomic and transcriptomic levels and applied it to obtain a list of candidate genetic risk factors for the iPD samples in our cohort.
Conclusions
Our results expand the knowledge about the PD risk variants and their biological functions as well as shed light on the underlying mechanism of pathogenesis, which could suggest novel therapeutic targets for PD.
GALC VARIANTS ARE ASSOCIATED WITH PARKINSON’S DISEASE AND WITH CHANGES IN ENZYMATIC ACTIVITY
Abstract
Aims
To identify the functional role of PD genome-wide association study (GWAS) top hit locus near GALC, encoding the lysosomal enzyme galactosylcerebrosidase(GALC).
Methods
GALC activity was measured in two cohorts, from Columbia University (N=1229) and PPMI (N=470). GALC activity measurements were performed at Sanofi laboratories by liquid chromatography-tandem/mass-spectrometry from dried blood spots. Using genotyping data from the Columbia University cohort (Illumina-OmniExpress array/NeuroX) and the PPMI cohort (NeuroX/Immunochip), we performed a GWAS to examine the effect of genetic variants on GALC activity. We further performed full sequencing of GALC in three independent cohorts at McGill University (PD,N=2421; controls,N=1625) to study the effects of rare variants. We performed Mendelian randomization to study the potential causal relationship between GALC activity and PD risk. Finally, we examined the effects of GALC variants on GALC structure in silico.
Results
The known PD risk variant rs979812 near GALC is associated with increased GALC activity (b=1.2; SE=0.06; p=5.10E-95). We did not find any variant significantly associated with GALC activity outside the GALC locus. Mendelian randomization suggested that increased GALC activity may be causal in PD (IVW; b=0.025; se=0.007; p=0.0008). Burden analyses did not identify an association of rare GALC variants in PD. Finally, structural analysis demonstrated that the common variant p.I562T can lead to improper maturation of GALC affecting its activity.
Conclusions
The risk of PD associated with the GALC locus is potentially driven by increased GALC activity. Furthermore, GALC activity may be causal in PD, and should therefore be studied as a potential therapeutic target.
GENOTYPE-PHENOTYPE CORRELATIONS IN BELGIAN CARRIERS OF PATHOGENIC TBK1 MUTATIONS
Abstract
Aims
Pathogenic TBK1 mutations are associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We report prevalence and phenotype of Belgian carriers of TBK1 mutations. We present a pedigree segregating a previously unknown LOF mutation with autosomal dominant inheritance, and carriers of genetic variants of uncertain significance.
Methods
Genetic screening of TBK1 in Belgian FTD (n = 678), ALS (n = 220) and FTD-ALS (n = 46) patient cohorts. We identified 18 carriers of pathogenic mutations and 1 carrier of a novel LOF mutation. Family members were sampled and screened. In total, we identified 40 carriers. Missense mutations of uncertain significance were observed in 6 patients. We collected data on clinical characteristics, biomarkers, and neuropathology.
Results
TBK1 LOF mutation frequency are 1.3% in FTD, 3.6% in ALS and 4.3% in FTD-ALS. Among 40 carriers, 23 were affected: FTD (n = 8; 7 bvFTD, 1 PPA), ALS (n = 7), unspecified dementia (n = 5), FTD-ALS (n = 2), Alzheimer’s disease (n = 1). Mean onset age and disease duration were 62.8 and 6.5 years (ranges 41-86 and 0-24 years). ALS patients had significantly shorter disease duration averaging 2.6 year. Neuropathology confirmed FTLD-TDP B. TBK1 missense mutations of uncertain significance were present in 3 ALS and 3 FTD patients (1 svPPA, 2 bvFTD).
Conclusions
Pathogenic TBK1 mutations are a frequent cause of FTD, ALS and particularly FTD plus ALS. The common phenotypes were FTD, ALS, unspecified dementia. Disease duration correlated with clinical phenotype. Brain autopsy revealed FTLD-TDP B.
ADMIXTURE MAPPING IDENTIFIES NOVEL ALZHEIMER DISEASE RISK REGIONS IN AFRICAN AMERICANS
Abstract
Aims
African American (AA) population with the admixed genetic ancestry provides a unique opportunity to identify novel genetic factors associated with Alzheimer's disease (AD) related to genetic ancestry. Admixture mapping provides a complementary and sometimes more powerful approach to SNP-based genome-wide association studies in admixed populations. This study used admixture mapping to prioritize the genetic regions associated with AD in AA individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions.
Methods
We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes.
Results
Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p=2.2 x10-5) and 18q21.33 (p=1.2x10-5). The ancestry-aware regression model identified a significant interaction term on chromosome 17p13.2 (p-value=7.93x10-5; parametric bootstrap FDR < 0.05). Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited 17p13.2 locus from their African ancestors.
Conclusions
We identified two novel AD risk genetic loci in AAs; however, the 17p13.2 region was identified as genome-wide significant in three previous meta-analysis studies in non-Hispanic White populations. Our fine-mapping of the chromosome 17p13.2 and 18q21.33 regions revealed several interesting genes, some of which have been implicated in AD risk, such as the MINK1, KIF1C, and BCL2.
A TAU-DEPENDENT MECHANISM OF EPIGENETIC MODULATION OF GENE EXPRESSION
Abstract
Aims
Explain the molecular mechanism of Tau-dependent epigenetic modification associated to neurodegeneration and causing heterochromatin loss in disease.
Methods
RNA-seq, Western Blot, Immunofluorescence Microscopy, Co-immunoprecipitation, qPCR, SA-βgalactosidase assay, FACS
Results
We discovered that a loss-of-function of Tau affects cell fate ultimately promoting a senescent state (Magrin et al, Commun Biol 3:245. 2020). We now report the outcome of an RNAseq analysis and the identification of a small set of genes up-regulated in Tau-KO cells when compared to parental, Tau-expressing cells. Bioinformatical analysis of their promotor regions points to a shared epigenetic mechanism of regulation. We also report a cell pathway implicated in the Tau-dependent induction of cellular senescence, a process implicated in neurodegeneration and cognitive decline in a tauopathy mouse model.
Conclusions
This new Tau function may provide a mechanism explaining heterochromatin loss in disease and advance our understanding of the molecular process leading to neurodegeneration.