4.7 Article

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

Journal

NATURE NEUROSCIENCE
Volume 24, Issue 7, Pages 941-953

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41593-021-00858-w

Keywords

-

Categories

Funding

  1. National Institutes of Health (NIH) [R00MH102357, U54EB020403, R01MH118349, R01MH120125]
  2. Brain Research Foundation
  3. NIH [R37 MH060233, R01 MH094714, UO1MH116489, R01 MH110927, P30 DK034987]
  4. UNC Neuroscience Center Microscopy Core [P30NS045892]
  5. UCLA CFAR [5P30 AI028697]
  6. PsychENCODE Consortium [U01MH103392, U01MH103365, U01MH103346, U01MH103340, U01MH103339, R21MH109956, R21MH105881, R21MH105853, R21MH103877, R21MH102791, R01MH111721, R01MH110928, R01MH110927, R01MH110926, R01MH110921, R01MH110920, R01MH110905, R01MH109715, R01MH109677, R01MH105898]
  7. The PsychENCODE Consortium [R01MH094714, P50MH106934, U01MH116488, U01MH116487, U01MH116492, U01MH116489, U01MH116438, U01MH116441, U01MH116442, R01MH114911, R01MH114899, R01MH114901, R01MH117293, R01MH117291, R01MH117292]
  8. NC TraCS Pilot funding

Ask authors/readers for more resources

Cell-type-specific chromatin accessibility QTL during neurogenesis allow fine mapping of causal variants, revealing regulatory mechanisms underlying noncoding loci associated with gene expression and neuropsychiatric disorders. Mutations disrupting transcriptional activators generally decrease chromatin accessibility, while mutations disrupting repressors increase chromatin accessibility.
Cell-type-specific chromatin accessibility QTL during neurogenesis allow fine mapping of causal variants and more complete underlying of regulatory mechanisms underlying noncoding loci associated with gene expression and neuropsychiatric disorders. 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available