Sites of active gene regulation in the prenatal frontal cortex and their role in neuropsychiatric disorders
© 2021 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC..
Common genetic variation appears to largely influence risk for neuropsychiatric disorders through effects on gene regulation. It is therefore possible to shed light on the biology of these conditions by testing for enrichment of associated genetic variation within regulatory genomic regions operating in specific tissues or cell types. Here, we have used the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) to map open chromatin (an index of active regulatory genomic regions) in bulk tissue, NeuN+ and NeuN- nuclei from the prenatal human frontal cortex, and tested enrichment of single-nucleotide polymorphism (SNP) heritability for five neuropsychiatric disorders (autism spectrum disorder, attention deficit hyperactivity disorder [ADHD], bipolar disorder, major depressive disorder, and schizophrenia) within these regions. We observed significant enrichment of SNP heritability for ADHD, major depressive disorder, and schizophrenia within open chromatin regions (OCRs) mapped in bulk fetal frontal cortex, and for all five tested neuropsychiatric conditions when we restricted these sites to those overlapping histone modifications indicative of enhancers (H3K4me1) or promoters (H3K4me3) in fetal brain. SNP heritability for neuropsychiatric disorders was significantly enriched in OCRs identified in fetal frontal cortex NeuN- as well as NeuN+ nuclei overlapping fetal brain H3K4me1 or H3K4me3 sites. We additionally demonstrate the utility of our mapped OCRs for prioritizing potentially functional SNPs at genome-wide significant risk loci for neuropsychiatric disorders. Our data provide evidence for an early neurodevelopmental component to a range of neuropsychiatric conditions and highlight an important role for regulatory genomic regions active within both NeuN+ and NeuN- cells of the prenatal brain.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:186 |
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| Enthalten in: |
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics - 186(2021), 6 vom: 01. Sept., Seite 376-388 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kouakou, Manuela R [VerfasserIn] |
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| Links: |
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| Themen: |
GWAS |
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| Anmerkungen: |
Date Completed 13.01.2022 Date Revised 13.01.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/ajmg.b.32877 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a Date Revised 13.01.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC. | ||
| 520 | |a Common genetic variation appears to largely influence risk for neuropsychiatric disorders through effects on gene regulation. It is therefore possible to shed light on the biology of these conditions by testing for enrichment of associated genetic variation within regulatory genomic regions operating in specific tissues or cell types. Here, we have used the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) to map open chromatin (an index of active regulatory genomic regions) in bulk tissue, NeuN+ and NeuN- nuclei from the prenatal human frontal cortex, and tested enrichment of single-nucleotide polymorphism (SNP) heritability for five neuropsychiatric disorders (autism spectrum disorder, attention deficit hyperactivity disorder [ADHD], bipolar disorder, major depressive disorder, and schizophrenia) within these regions. We observed significant enrichment of SNP heritability for ADHD, major depressive disorder, and schizophrenia within open chromatin regions (OCRs) mapped in bulk fetal frontal cortex, and for all five tested neuropsychiatric conditions when we restricted these sites to those overlapping histone modifications indicative of enhancers (H3K4me1) or promoters (H3K4me3) in fetal brain. SNP heritability for neuropsychiatric disorders was significantly enriched in OCRs identified in fetal frontal cortex NeuN- as well as NeuN+ nuclei overlapping fetal brain H3K4me1 or H3K4me3 sites. We additionally demonstrate the utility of our mapped OCRs for prioritizing potentially functional SNPs at genome-wide significant risk loci for neuropsychiatric disorders. Our data provide evidence for an early neurodevelopmental component to a range of neuropsychiatric conditions and highlight an important role for regulatory genomic regions active within both NeuN+ and NeuN- cells of the prenatal brain | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a GWAS | |
| 650 | 4 | |a gene expression | |
| 650 | 4 | |a gene regulation | |
| 650 | 4 | |a psychiatric genetics | |
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| 700 | 1 | |a Cameron, Darren |e verfasserin |4 aut | |
| 700 | 1 | |a Hannon, Eilis |e verfasserin |4 aut | |
| 700 | 1 | |a Dempster, Emma L |e verfasserin |4 aut | |
| 700 | 1 | |a Mill, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Hill, Matthew J |e verfasserin |4 aut | |
| 700 | 1 | |a Bray, Nicholas J |e verfasserin |4 aut | |
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