Frank Soldner, from the Whitehead Institute for Biomedical Research, having previously generated isogenic hiPSCs at two-point mutations in early-onset Parkinson’s disease (PD) (Soldner et al., 2011), now presented studies on the penetrance of non-coding PD risk alleles. Meta-analysis of genome-wide association study (GWAS) data from 13,708 PD cases has identified 26 significant PD-associated loci; however, there is a lack of mechanistic insight in how such sequence variants functionally contribute to complex disease. Soldner proposed that functional disruption of distal enhancer elements leads to the deregulation of gene expression and confers susceptibility to PD. As a proof of principle to study the consequence of these mutations on gene expression, he conducted functional analysis of cis-regulatory elements in the SNCA locus via genome editing tools in order to precisely disrupt regulatory elements in isogenic pairs. He used quantitative allele-specific assays as readouts and showed that common single nucleotide polymorphisms (SNPs) with small effect size can contribute to PD risk. This work highlights the importance of correlating previously identified disease-related mutations (SNPs and CNVs) with changes in expression profile in vitro in order to identify functional disease-relevant risk variants and determine the mutation’s impact.
