中央研究院 資訊科學研究所

Prof. Gerard D. Schellenberg : Tauopathy Genetics: Alzheimer's Disease and Progressive supranuclear palsy

Prof. Li-San Wang  : Deciphering the Genetic Architecture of Alzheimer's Disease

 

Alzheimer’s disease is the most common form of dementia and affects tens of millions of people around the world. Characterized by extensive brain atrophy, the disease leads gradual loss of memory, speech, and executive functions over up to ten years until the patient becomes incapacitated and completely dependent upon caregivers.

Despite a century of research, there is no effective means to treat or manage Alzheimer's Disease (AD), in part because we do not fully understand its cause.  AD is highly heritable, and deciphering the genetic landscape of the disease may lead to new insight into the cellular processes that lead to neurodegeneration and novel targets for drug discovery.

Genome-wide association studies (GWAS) have identified dozens of common and rare variants associated with AD risk.  Many of these signals do not alter protein sequences and are presumed to perturb expression levels of neighboring genes, some up to 1Mb away.  To identify the underlying regulatory mechanisms, we developed INFERNO (INFERring the molecular mechanisms of NOncoding genetic variants), a novel method which integrates hundreds of functional genomics datasets

spanning enhancer activity, transcription factor binding sites, and expression quantitative trait loci with GWAS summary statistics.

INFERNO identified enhancer dysregulation in all 19 regions of the2013 IGAP study, found significant enrichments of enhancer overlaps in the immune-related blood category, and co-localized eQTL signals overlapping enhancers from the matching tissue class in ten regions.

We validated the allele-specific effects of several variants on enhancer function using luciferase expression assays.

 

I will also introduce the Alzheimer's Disease Sequencing Project (ADSP).

ADSP is among the largest genome sequencing projects in the world. The project is in its third phase and will sequence up to 25,000 whole genomes from different populations.  I will present the study design, challenges and our solutions in data generation and analysis, and how to access the ADSP data and findings.