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In the post genome-wide association studies (GWAS) era we are shifting gears toward translation of genetic disease loci to molecular mechanisms of pathogenesis and pinpointing the causal genetic factors and their functional effects. It has been suggested that changes, even subtle, in the expression levels of wild-type genes in the brain can, over years, lead to neurodegenerative diseases. Moreover, differences in gene expression profiles between brain tissues from neurodegenerative disease patients compared to healthy controls have been reported. Short structural variants (SSVs) are short genomic variants (<50 bp) other than SNPs. Recently, there has been increased support for the idea that SSVs, which are largely ignored in large-scale genetic studies, may be involved in many complex diseases, and may also contribute significantly to variation in gene expression in human. We have been studying the expression regulation of key genes implicated in Alzheimer’s (AD) and Parkinson’s (PD) diseases and a wide-spectrum of related disorders. In particular, we focus on noncoding SSVs and their cis-regulatory effects on gene expression using a comprehensive strategy that combines multiple-level approaches. (1) in silico: we have developed a new bioinformatics tool for prioritizing candidate functional/causal SSVs. The tool is a searchable, annotated database of SSVs, with associated customizable scoring software that is designed to evaluate and prioritize SSVs that are most likely to have significant biological effects and impact on disease risk. (2) in vitro: we have established induced Pluripotent Stem Cell (iPSC)-derived neurons, dopaminergic and cholinergic, from a normal subject and PD patients. We are currently using this model system to determine how cis-variants modulate expression of disease risk genes via their interactions with the trans-acting factors, by applying CRISPR/Cas9 – mediated genome editing. (3) in vivo: we have quantified cell-type specific gene expression in neurons, astrocytes, and microglia by single-cell gene expression assays using cells isolated from frozen human brain samples via LCM. We have implemented this strategy in studies of genomic loci implicated in Lewy body and AD diseases, specifically SNCA gene and the TOMM40-APOE cluster. Collectively, the innovative approaches we developed represent a cohesive strategy for discovering potentially functional and causal variants within candidate risk-genes associated with AD-PD spectrum disorders.