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

Publication ,  Journal Article
Liang, D; Elwell, AL; Aygün, N; Krupa, O; Wolter, JM; Kyere, FA; Lafferty, MJ; Cheek, KE; Courtney, KP; Yusupova, M; Garrett, ME; Crawford, GE ...
Published in: Nat Neurosci
July 2021

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.

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Published In

Nat Neurosci

DOI

EISSN

1546-1726

Publication Date

July 2021

Volume

24

Issue

7

Start / End Page

941 / 953

Location

United States

Related Subject Headings

  • Transcription Factors
  • Regulatory Elements, Transcriptional
  • Quantitative Trait Loci
  • Neurons
  • Neurology & Neurosurgery
  • Neurogenesis
  • Neural Stem Cells
  • Mental Disorders
  • Humans
  • Genome-Wide Association Study
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Liang, D., Elwell, A. L., Aygün, N., Krupa, O., Wolter, J. M., Kyere, F. A., … Stein, J. L. (2021). Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation. Nat Neurosci, 24(7), 941–953. https://doi.org/10.1038/s41593-021-00858-w
Liang, Dan, Angela L. Elwell, Nil Aygün, Oleh Krupa, Justin M. Wolter, Felix A. Kyere, Michael J. Lafferty, et al. “Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation.Nat Neurosci 24, no. 7 (July 2021): 941–53. https://doi.org/10.1038/s41593-021-00858-w.
Liang D, Elwell AL, Aygün N, Krupa O, Wolter JM, Kyere FA, et al. Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation. Nat Neurosci. 2021 Jul;24(7):941–53.
Liang, Dan, et al. “Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation.Nat Neurosci, vol. 24, no. 7, July 2021, pp. 941–53. Pubmed, doi:10.1038/s41593-021-00858-w.
Liang D, Elwell AL, Aygün N, Krupa O, Wolter JM, Kyere FA, Lafferty MJ, Cheek KE, Courtney KP, Yusupova M, Garrett ME, Ashley-Koch A, Crawford GE, Love MI, de la Torre-Ubieta L, Geschwind DH, Stein JL. Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation. Nat Neurosci. 2021 Jul;24(7):941–953.

Published In

Nat Neurosci

DOI

EISSN

1546-1726

Publication Date

July 2021

Volume

24

Issue

7

Start / End Page

941 / 953

Location

United States

Related Subject Headings

  • Transcription Factors
  • Regulatory Elements, Transcriptional
  • Quantitative Trait Loci
  • Neurons
  • Neurology & Neurosurgery
  • Neurogenesis
  • Neural Stem Cells
  • Mental Disorders
  • Humans
  • Genome-Wide Association Study