Research Fahri Küçükali

Abstract

Alzheimer's disease (AD) is the most common form of dementia and a complex neurodegenerative disease with strong genetic component. We performed a genome-wide association study (GWAS) of AD and identified an unpreceded number of 42 new risk loci, in which I prioritized risk genes and AD-associated molecular alterations in majority of risk loci mainly by integrating molecular quantitative trait loci (QTL) with GWAS. In this project I propose to expand these analyses with a set of new approaches, focusing on genetically unresolved loci and understudied brain molecular phenotypes. These approaches include (i) fine-mapping associations to identify likely causal variants and optimizing GWAS-QTL colocalization, (ii) long-read targeted DNA sequencing of 9 unresolved loci to reveal GWAS-linked structural variants, DNA methylation and chromatin accessibility alterations, and (iii) characterizing brain cell-type and allele-specific transcript structure and abundance through long-read single-nuclei RNA sequencing. With these, I hypothesize that the majority of association signals will be explained and mapped to a set of prioritized variants, genes, mechanisms, and cell types. This will greatly contribute to our understanding of AD genetic risk, which consequently may lead to development of better diagnosis, risk stratification, and therapeutic opportunities.

Researcher(s)

• Promoter: Sleegers Kristel
• Fellow: Küçükali Fahri

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is an important threat to both personal and publich health. Familial clustering of AD has long been known, and in the past few decades, important progress has been made in unraveling the genetics of AD. For patients and their relatives today, the most tangible benefit of this progress is the ability to genetically diagnose or predict the disease. Nevertheless, this only applies to a minority of families, in which a mutation in APP, PSEN1 or PSEN2 has been identified that causes a rare autosomal dominant form of AD. For the majority of patients, the disease has a complex genetic background, which cannot be readily translated into accurate risk prediction. Remarkable in this light is our recent observation that rare predicted loss-of-function mutations in the AD risk gene ABCA7 are associated with autosomal dominant pattern of inheritance of AD. Multiplex AD families segregating such rare variants represent a distinct subgroup in which some of the benefits of genetic testing may hold true. The key aim of this PhD project is to get a better understanding of the role of these rare risk variants in familial clustering of AD, with the ultimate goal to assess if and how the knowledge of carrier status of such a variant can be used in genetic risk prediction. A variety of state-of-the-art approaches will be used to address this aim. Molecular characterization of rare variants through RNA sequencing analysis of lymphoblast cell lines and brain will contribute to a better understanding of the impact of the mutations, as well as a delineation of neutral and pathogenic variants. Genetic-epidemiological characterization through DNA sequencing on additional cohorts will shed further light on the frequency and penetrance of these mutations. The mode of action and causes of phenotypic heterogeneity will be investigated in derivatives of induced pluripotent stem cells of mutation carriers. Finally, this patient-derived model will be used to investigate the potential of compounds to modify the effect of the mutation, eventually enabling targeted treatment. This PhD project covers an uncharted but promising territory in the battle against AD, particularly considering the increasing focus in this battle on patient stratification, early detection and precision medicine.

Researcher(s)

• Promoter: Sleegers Kristel
• Fellow: Küçükali Fahri

Research team(s)

Project type(s)

• Research Project