In Vitro Modeling of Complex Neurological Diseases

Abstract

A major reason for the lack of effective therapeutics and a deep biological understanding of complex diseases, which are thought to result from a complex interaction between genetic and environmental risk factors, is the paucity of relevant experimental models. This review describes a novel experimental approach that allows the study of the functional effects of disease-associated risk in complex disease by combining genome wide association studies (GWAS) and genome–scale epigenetic data to prioritize disease-associated risk variants with efficient gene editing technologies in human pluripotent stem cells (hPSCs). As a proof of principle, we recently used such a genetically precisely controlled experimental system to identify a common Parkinson’s disease-associated risk variant in a non-coding distal enhancer element that alters the binding of transcription factors and regulates the expression of α-synuclein (SNCA), a key gene implicated in the pathogenesis of Parkinson’s disease.