Sites of active gene regulation in the prenatal frontal cortex and their role in neuropsychiatric disorders
Sites of active gene regulation in the prenatal frontal cortex and their role in neuropsychiatric disorders
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产前额叶皮层的活跃基因调控位点及其在神经精神疾病中的作用
DOI：
10.1101/2021.09.01.458548
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Kouakou M
中科院分区：
文献类型：
--
作者：
Kouakou M
常见的遗传变异似乎在很大程度上通过影响基因调控影响神经精神疾病的风险。因此，有可能通过检测在特定组织或细胞类型中操作的调控基因组区域内相关遗传变异的富集来阐明这些条件的生物学。在这里，我们使用高通量测序的转座酶可接近染色质测定法（ATAC-Seq）绘制开放染色质图谱（活性调控基因组区域的指数），来自产前人类额叶皮质的大块组织NeuN+和NeuN−核，并测试了五种神经精神疾病的单核苷酸多态性（SNP）遗传性的富集（自闭症谱系障碍、注意力缺陷多动障碍[ADHD]、双相情感障碍、重度抑郁症和精神分裂症）。我们观察到显着丰富的SNP遗传性多动症，重性抑郁症，精神分裂症的开放染色质区域（OCR）映射在散装胎儿额叶皮层，并为所有五个测试的神经精神疾病时，我们限制这些网站的重叠组蛋白修饰指示增强子（H3 K4 me 1）或启动子（H3 K4 me 3）在胎儿大脑。神经精神疾病的SNP遗传性在胎儿额叶皮质NeuN−以及重叠胎儿脑H3 K4 me 1或H3 K4 me 3位点的NeuN+核中鉴定的OCR中显著富集。我们还证明了我们绘制的OCR在神经精神疾病的全基因组显著风险位点上优先考虑潜在功能SNP的效用。我们的数据为一系列神经精神疾病的早期神经发育成分提供了证据，并强调了产前大脑NeuN+和NeuN−细胞内活跃的调控基因组区域的重要作用。
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.
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影响因子：
64.8
作者：
Roadmap Epigenomics Consortium;Kundaje A;Meuleman W;Ernst J;Bilenky M;Yen A;Heravi-Moussavi A;Kheradpour P;Zhang Z;Wang J;Ziller MJ;Amin V;Whitaker JW;Schultz MD;Ward LD;Sarkar A;Quon G;Sandstrom RS;Eaton ML;Wu YC;Pfenning AR;Wang X;Claussnitzer M;Liu Y;Coarfa C;Harris RA;Shoresh N;Epstein CB;Gjoneska E;Leung D;Xie W;Hawkins RD;Lister R;Hong C;Gascard P;Mungall AJ;Moore R;Chuah E;Tam A;Canfield TK;Hansen RS;Kaul R;Sabo PJ;Bansal MS;Carles A;Dixon JR;Farh KH;Feizi S;Karlic R;Kim AR;Kulkarni A;Li D;Lowdon R;Elliott G;Mercer TR;Neph SJ;Onuchic V;Polak P;Rajagopal N;Ray P;Sallari RC;Siebenthall KT;Sinnott-Armstrong NA;Stevens M;Thurman RE;Wu J;Zhang B;Zhou X;Beaudet AE;Boyer LA;De Jager PL;Farnham PJ;Fisher SJ;Haussler D;Jones SJ;Li W;Marra MA;McManus MT;Sunyaev S;Thomson JA;Tlsty TD;Tsai LH;Wang W;Waterland RA;Zhang MQ;Chadwick LH;Bernstein BE;Costello JF;Ecker JR;Hirst M;Meissner A;Milosavljevic A;Ren B;Stamatoyannopoulos JA;Wang T;Kellis M
通讯作者：
Kellis M
影响因子：
64.8
作者：
通讯作者：
--
表达数量性状基因座
DOI：
10.32388/14magl
发表时间：
2020
期刊：
Definitions
影响因子：
--
作者：
B. Descours;G. Petitjean;José;T. Bruel;Raoul Raffel;C. Psomas;J. Reynes;C. Lacabaratz;Y. Lévy;O. Schwartz;J. Lelièvre;M. Benkirane
通讯作者：
M. Benkirane
影响因子：
7
作者：
Song, Lingyun;Zhang, Zhancheng;Furey, Terrence S.
通讯作者：
Furey, Terrence S.
影响因子：
48
作者：
Buenrostro, Jason D.;Giresi, Paul G.;Zaba, Lisa C.;Chang, Howard Y.;Greenleaf, William J.
通讯作者：
Greenleaf, William J.