Integrative analysis of 3604 GWAS reveals multiple novel cell type-specific regulatory associations.
Integrative analysis of 3604 GWAS reveals multiple novel cell type-specific regulatory associations.
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DOI：
10.1186/s13059-021-02560-3
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发表时间：
2022-01-07
期刊：
影响因子：
12.3
通讯作者：
Berndt SI
中科院分区：
文献类型：
--
作者：
Breeze CE;Haugen E;Reynolds A;Teschendorff A;van Dongen J;Lan Q;Rothman N;Bourque G;Dunham I;Beck S;Stamatoyannopoulos J;Franceschini N;Berndt SI
全基因组关联研究（GWAS）的单核苷酸多态性（SNP）是已知的优先共定位到组织和细胞类型中的活性调控元件与疾病病因学相关。相关细胞类型特异性调节的进一步表征可以拓宽我们对GWAS信号如何导致疾病风险的理解。为了深入了解GWAS关联的潜在功能机制，我们开发了FORGE 2（https：//forge2.altiusinstitute.org/），这是FORGE网络工具的更新版本。FORGE 2使用细胞类型特异性调控元件注释的扩展图谱，包括DNA酶I热点，5个组蛋白标记类别和15个隐马尔可夫模型（HMM）染色质状态，以识别组织和细胞类型特异性信号。来自NHGRI-EBI GWAS目录的3，604个GWAS的分析产生了2，057个GWAS的至少一个显著疾病/性状-组织关联，包括免疫组织和细胞类型中表观基因组标记特异性的> 400个关联，心脏组织特异性的> 30个关联，以及脑组织特异性的> 60个关联，突出了组织和细胞类型特异性调控元件的关键潜力。重要的是，我们证明了FORGE 2分析可以将先前观察到的可访问的染色质富集分离成不同的染色质状态，例如增强子或活性转录起始位点，从而更好地了解潜在的调控机制。有趣的是，还检测到抑制性染色质状态和组蛋白标记的组织特异性富集，表明组织特异性抑制区域在GWAS介导的疾病病因学中的作用。总之，我们证明了FORGE 2有可能发现以前未报道的疾病组织关联并确定新的候选机制。FORGE 2是一个透明的，用户友好的网络工具，用于从GWAS发现的基因座的综合分析。在线版本包含补充材料，可通过10.1186/s13059-021-02560-3获得。
Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are known to preferentially co-locate to active regulatory elements in tissues and cell types relevant to disease aetiology. Further characterisation of associated cell type-specific regulation can broaden our understanding of how GWAS signals may contribute to disease risk. To gain insight into potential functional mechanisms underlying GWAS associations, we developed FORGE2 (https://forge2.altiusinstitute.org/), which is an updated version of the FORGE web tool. FORGE2 uses an expanded atlas of cell type-specific regulatory element annotations, including DNase I hotspots, five histone mark categories and 15 hidden Markov model (HMM) chromatin states, to identify tissue- and cell type-specific signals. An analysis of 3,604 GWAS from the NHGRI-EBI GWAS catalogue yielded at least one significant disease/trait-tissue association for 2,057 GWAS, including > 400 associations specific to epigenomic marks in immune tissues and cell types, > 30 associations specific to heart tissue, and > 60 associations specific to brain tissue, highlighting the key potential of tissue- and cell type-specific regulatory elements. Importantly, we demonstrate that FORGE2 analysis can separate previously observed accessible chromatin enrichments into different chromatin states, such as enhancers or active transcription start sites, providing a greater understanding of underlying regulatory mechanisms. Interestingly, tissue-specific enrichments for repressive chromatin states and histone marks were also detected, suggesting a role for tissue-specific repressed regions in GWAS-mediated disease aetiology. In summary, we demonstrate that FORGE2 has the potential to uncover previously unreported disease-tissue associations and identify new candidate mechanisms. FORGE2 is a transparent, user-friendly web tool for the integrative analysis of loci discovered from GWAS. The online version contains supplementary material available at 10.1186/s13059-021-02560-3.
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通讯作者：
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