Genetic associations of breast and prostate cancer are enriched for regulatory elements identified in disease-related tissues
Genetic associations of breast and prostate cancer are enriched for regulatory elements identified in disease-related tissues
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DOI：
10.1007/s00439-019-02041-5
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发表时间：
2019-10-01
期刊：
影响因子：
5.3
通讯作者：
Lindstrom, Sara
中科院分区：
文献类型：
--
作者：
Chen, Hongjie;Kichaev, Gleb;Lindstrom, Sara
尽管全基因组关联研究（GWAS）已经确定了数百个乳腺癌和前列腺癌的风险位点，但只有少数研究描述了功能基因组注释中的GWAS关联信号，特别关注位于DNA调节元件中的单核苷酸多态性（SNP）。在这项研究中，我们研究了乳腺癌和前列腺癌的GWAS信号在正常组织和癌细胞系中的基因组功能区域的富集模式。我们量化了在监管类别中与乳腺癌和前列腺癌相关p值< 1 x 10（-8）的SNP的总体富集。然后，我们获得了DNaseI超敏位点（DHS）、典型增强子和多种组织类型的超级增强子的注释，以评估在疾病相关组织中发现的注释中是否选择性富集了显著的GWAS信号。最后，我们量化了乳腺癌和前列腺癌SNP遗传力在调控区的富集，并将SNP遗传力的富集模式与GWAS信号进行了比较。观察到在乳腺癌细胞系MCF-7中鉴定的DHS、典型增强子和超级增强子具有乳腺癌的全基因组显著变体的最高富集。对于前列腺癌，GWAS信号主要富集在DHS和在前列腺癌细胞系LNCaP中鉴定的典型增强子中。随着GWAS p值阈值的逐步严格，在DHS、典型增强子和位于疾病相关组织中的超级增强子中观察到两种疾病的富集趋势增加。遗传富集分析的结果支持乳腺癌和前列腺癌疾病相关细胞系中功能基因组区域的选择性富集模式。我们的研究结果表明，在表征GWAS结果时，研究疾病相关组织中识别的功能注释的重要性，并进一步证明了来自疾病相关组织的生殖系DNA调控元件在乳腺癌和前列腺癌发生中的作用。
Although genome-wide association studies (GWAS) have identified hundreds of risk loci for breast and prostate cancer, only a few studies have characterized the GWAS association signals across functional genomic annotations with a particular focus on single nucleotide polymorphisms (SNPs) located in DNA regulatory elements. In this study, we investigated the enrichment pattern of GWAS signals for breast and prostate cancer in genomic functional regions located in normal tissue and cancer cell lines. We quantified the overall enrichment of SNPs with breast and prostate cancer association p values < 1 x 10(-8) across regulatory categories. We then obtained annotations for DNaseI hypersensitive sites (DHS), typical enhancers, and super enhancers across multiple tissue types, to assess if significant GWAS signals were selectively enriched in annotations found in disease-related tissue. Finally, we quantified the enrichment of breast and prostate cancer SNP heritability in regulatory regions, and compared the enrichment pattern of SNP heritability with GWAS signals. DHS, typical enhancers, and super enhancers identified in the breast cancer cell line MCF-7 were observed with the highest enrichment of genome-wide significant variants for breast cancer. For prostate cancer, GWAS signals were mostly enriched in DHS and typical enhancers identified in the prostate cancer cell line LNCaP. With progressively stringent GWAS p value thresholds, an increasing trend of enrichment was observed for both diseases in DHS, typical enhancers, and super enhancers located in disease-related tissue. Results from heritability enrichment analysis supported the selective enrichment pattern of functional genomic regions in disease-related cell lines for both breast and prostate cancer. Our results suggest the importance of studying functional annotations identified in disease-related tissues when characterizing GWAS results, and further demonstrate the role of germline DNA regulatory elements from disease-related tissue in breast and prostate carcinogenesis.