The main goal of my research is to apply functional genomic approaches in human cells to elucidating the molecular and cellular mechanisms of complex neurological disorders such as Alzheimer’s and Parkinson’s disease. One of the major challenges of studying human complex diseases is the lack of relevant model systems that combine known genetic elements with disease-associated phenotypic readouts. This is particularly problematic for many common medical conditions including sporadic neurodegenerative diseases, which have no well-defined genetic etiology and do not follow Mendelian inheritance patterns. Epidemiology and population genetics suggest that such sporadic diseases result from a complex interaction between multiple genetic and non-genetic (lifestyle and environmental) risk factors. And although genome wide association studies (GWASs) have identified sequence variants such as single nucleotide polymorphisms (SNPs), deletions and insertions associated with a wide variety of neurological disease, the vast majority of these risk variants have no established biological relevance to disease or clinical utility for prognosis or treatment. This complexity and our limited knowledge of the underlying genetic factors have impeded our understanding of the molecular mechanisms of many complex diseases and, more importantly, limited the development of effective therapeutics. 

Three major recent innovations have fundamentally changed our ability to study human neurological diseases in a cell culture dish: (i) Reprogramming of somatic cells into human induced pluripotent stem cells (hiPSCs) to generate patient-derived disease-relevant neuronal cells, (ii) the development of genome engineering technologies such as the CRISPR/Cas9 system to modify the genome in human cells and (iii) the availability of tissue-type and disease-specific genome-scale genetic and epigenetic information. Our previous work has demonstrated that integration of population genetic and genome-wide epigenetic data combined with hiPSC and gene editing technologies now enables us to dissect the functional effects of genetic risk variants in order to study human neurological disorders in a genetically controlled and systematic manner. My lab is applying this novel experimental framework to systematically link GWAS-identified sequence variants to non-coding cis-regulatory elements and establish functional assays to connect diseases-associated risk alleles with the expression of disease-relevant effector genes and cellular phenotypes. Such disease-relevant phenotypic readouts allow us to perform unbiased chemical compound and CRISPR/Cas9-based genome-scale genetic screens to identify novel disease modifiers in human neuronal cells.

Furthermore, one of the emerging challenges in the human genetics field is to understand how genetic signals from multiple risk variants interact and collectively contribute to the development of diseases or confer susceptibility to aging and additional environmental factors. The generation of genetically defined human cellular models carrying various risk variants provide a human in vitro model system to investigate how genetic, epigenetic and environmental factors are integrated to contribute to disease development and progression.