Large-scale identification of the regulatory potential of SNPs in human neural stem cells

GWAS have identified thousands of 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 perform a massively parallel reporter assay called SuRE in human neural stem cells to assess the transcriptional regulatory potential of 7.1 million SNPs. We identify 7,002 SNPs with regulatory potential (emVars) among the 484,057 SNPs with sufficiently high expression. These emVars are enriched in enhancers and often coincide with binding sites for transcription factors, such as ZBTB33, YY1, and ETS factors.

We overlap SuRE data with eQTL data to pinpoint likely gene-regulatory variants. Additionally, combining SuRE data with GWAS for seven neuropsychiatric phenotypes identifies 187 emVars 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 complex human phenotypes.

The authors thank Ludo Pagie for help with data processing. E.K., E.S.v.Z. and N.H.M.K. were supported by ZonMw Open grant 09120012010099, M.P.d.A. was supported by an ALW-open program grant (ALWOP.372) from NWO. These authors contributed equally: Eline Koornstra, Eva S. van Zanten, Noud H.

Department of Developmental Biology, Erasmus MC, Rotterdam, the Netherlands Eline Koornstra, Lize Meert, Mariana Pelicano de Almeida, Mike R. Poot Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands Oncode Institute, Utrecht, the Netherlands Noud H. Klaassen, Miguel Martinez-Ara, Mathias Eder & Bas van Steensel Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, the Netherlands Latin American Brain Health Institute (BrainLat), Universidad Adolfo Ibañez, Santiago, Chile Correspondence to Hieab H.

Adams, Bas van Steensel or Raymond A. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.