Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation

Nat Neurosci. 2021 Jul;24(7):941-953. doi: 10.1038/s41593-021-00858-w. | PubMed

Dan Liang^1,2, Angela L Elwell^1,2, Nil Aygün^1,2, Oleh Krupa^1,2, Justin M Wolter^1,2, Felix A Kyere^1,2, Michael J Lafferty^1,2, Kerry E Cheek^1,2, Kenan P Courtney^1,2, Marianna Yusupova^3,4,5, Melanie E Garrett⁶, Allison Ashley-Koch^6,7, Gregory E Crawford^8,9, Michael I Love^1,10, Luis de la Torre-Ubieta^3,4,5,11, Daniel H Geschwind^3,4,5,11, Jason L Stein^12,13

1. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
2. UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
3. Neurogenetics Program, Department of Neurology, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA, USA.
4. Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA, USA.
5. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
6. Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
7. Department of Medicine, Duke University, Durham, NC, USA.
8. Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
9. Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, USA.
10. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
11. Department of Psychiatry and Biobehavioral Sciences, Semel Institute, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA, USA.
12. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jason_stein@med.unc.edu.
13. UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jason_stein@med.unc.edu.

Abstract

Common genetic risk for neuropsychiatric disorders is enriched in regulatory elements active during cortical neurogenesis. However, it remains poorly understood as to how these variants influence gene regulation. To model the functional impact of common genetic variation on the noncoding genome during human cortical development, we performed the assay for transposase accessible chromatin using sequencing (ATAC-seq) and analyzed chromatin accessibility quantitative trait loci (QTL) in cultured human neural progenitor cells and their differentiated neuronal progeny from 87 donors. We identified significant genetic effects on 988/1,839 neuron/progenitor regulatory elements, with highly cell-type and temporally specific effects. A subset (roughly 30%) of chromatin accessibility-QTL were also associated with changes in gene expression. Motif-disrupting alleles of transcriptional activators generally led to decreases in chromatin accessibility, whereas motif-disrupting alleles of repressors led to increases in chromatin accessibility. By integrating cell-type-specific chromatin accessibility-QTL and brain-relevant genome-wide association data, we were able to fine-map and identify regulatory mechanisms underlying noncoding neuropsychiatric disorder risk loci.