Massively parallel assessment of gene regulatory activity at human cortical-structure-associated variants.

Genetic association studies have identified hundreds of largely noncoding loci associated with interindividual differences in the structure of the human cortex, although the specific functional variants contributing to these phenotypes are unknown. Here we implemented a massively parallel reporter assay to measure the regulatory activity of 9,092 cortical-structure-associated variants in human neural progenitor cells at baseline and during Wnt stimulation. We identified 918 variants with regulatory potential from 150 cortical-structure-associated loci (76% of loci studied), of which more than 50% showed allelic effects. Wnt stimulation modified regulatory activity at a subset of loci, revealing condition-dependent enhancers. Massively parallel reporter assay activity was largely induced by Alu elements, suggesting that they contribute to cortical expansion. The region-specific impact of motif-disrupting variants is probably mediated by spatially localized transcription factor expression during development. Together, these results provide a genome-scale functional framework for understanding how noncoding variation influences cortical structure.