Identifying the regulatory potential of 7 million SNPs in human neural stem cells

Genome-wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) associated with different human phenotypes. Most SNPs are located in non-coding regions of the genome, where a small subset of causal SNPs is thought to contribute to risk by regulating transcription. However, identification of such causal variants remains challenging due to linkage disequilibrium, where blocks of SNPs are inherited together. Here, we performed a massively parallel reporter assay called survey of regulatory elements (SuRE) in human neural stem cells to assess the transcription regulatory potential of 7.1 million SNPs. We identified 7,002 SNPs with regulatory potential (reporter assay quantitative trait loci, raQTLs), thereby increasing the number of putative regulatory variants in neural cell types by one order of magnitude. raQTLs were enriched for enhancers and often coincide with binding sites for transcription factors, such as ZBTB33, YY1, and ETS factors. Overlapping SuRE data with eQTL data pinpointed likely gene-regulatory variants. Overlap with GWAS for seven neuropsychiatric phenotypes identified 187 raQTLs in risk loci containing 183,186 SNPs assessed by SuRE. In conclusion, our SuRE dataset provides a rich source to prioritize genetic variants that may be relevant for disease. Overall design: human neural stem cells (hNSCs) were transfected with SuRE plasmid libraries. These SuRE plasmid libraries contain millions of genomic DNA fragments upstream of a unique barcode. Barcode sequencing after library transfection will yield 'autonomous promoter activity' from all of these fragments.