PT  - JOURNAL ARTICLE
AU  - Chengyu Deng
AU  - Sean Whalen
AU  - Marilyn Steyert
AU  - Ryan Ziffra
AU  - Pawel F. Przytycki
AU  - Fumitaka Inoue
AU  - Daniela A. Pereira
AU  - Davide Capauto
AU  - Scott Norton
AU  - Flora M. Vaccarino
AU  - Alex Pollen
AU  - Tomasz J. Nowakowski
AU  - Nadav Ahituv
AU  - Katherine S. Pollard
TI  - Massively parallel characterization of psychiatric disorder-associated and cell-type-specific regulatory elements in the developing human cortex
AID  - 10.1101/2023.02.15.528663
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.02.15.528663
4099  - http://biorxiv.org/content/early/2023/02/15/2023.02.15.528663.short
4100  - http://biorxiv.org/content/early/2023/02/15/2023.02.15.528663.full
AB  - Nucleotide changes in gene regulatory elements are important determinants of neuronal development and disease. Using massively parallel reporter assays in primary human cells from mid-gestation cortex and cerebral organoids, we interrogated the cis-regulatory activity of 102,767 sequences, including differentially accessible cell-type specific regions in the developing cortex and single-nucleotide variants associated with psychiatric disorders. In primary cells, we identified 46,802 active enhancer sequences and 164 disorder-associated variants that significantly alter enhancer activity. Activity was comparable in organoids and primary cells, suggesting that organoids provide an adequate model for the developing cortex. Using deep learning, we decoded the sequence basis and upstream regulators of enhancer activity. This work establishes a comprehensive catalog of functional gene regulatory elements and variants in human neuronal development.One Sentence Summary We identify 46,802 enhancers and 164 psychiatric disorder variants with regulatory effects in the developing cortex and organoids.Competing Interest StatementNA is the cofounder and on the scientific advisory board of Regel Therapeutics and receives funding from BioMarin Pharmaceutical Incorporated.