Genome-wide association studies (GWAS) have identified more than 140 prostate cancer (PrCa) risk regions which provide potential insights into causal mechanisms. Multiple lines of evidence show that a significant proportion of PrCa risk can be explained by germline causal variants that dysregulate nearby target genes in prostate-relevant tissues thus altering disease risk. The traditional approach to explore this hypothesis has been correlating GWAS variants with steady-state transcript levels, referred to as expression quantitative trait loci (eQTLs). In this work, we assess the utility of chromosome conformation capture (3C) coupled with immunoprecipitation (HiChIP) to identify target genes for PrCa GWAS risk loci. We find that interactome data confirms previously reported PrCa target genes identified through GWAS/eQTL overlap (e.g., MLPH). Interestingly, HiChIP identified links between PrCa GWAS variants and genes well-known to play a role in prostate cancer biology (e.g., AR) that are not detected by eQTL-based methods. We validate these findings through CRISPR interference (CRISPRi) perturbation of the variant-containing regulatory elements for NKX3-1 and AR in the LNCaP cell line. Our results demonstrate that looping data harbor additional information beyond eQTLs and expand the number of PrCa GWAS loci that can be linked to candidate susceptibility genes.

中文翻译：

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前列腺细胞系中的H3k27ac-HiChIP识别前列腺癌易感性的风险基因

全基因组关联研究（GWAS）已鉴定出140多个前列腺癌（PrCa）危险区域，这些区域可提供对因果机制的潜在见解。多条证据表明，PrCa风险的很大一部分可以通过种系因果变异体来解释，这些变异使前列腺相关组织中附近的靶基因失调，从而改变了疾病风险。探索该假设的传统方法是将GWAS变体与稳态转录本水平相关联，称为表达定量性状基因座（eQTL）。在这项工作中，我们评估染色体构象捕获（3C）结合免疫沉淀（HiChIP）的效用，以鉴定PrCa GWAS风险基因座的靶基因。我们发现，相互作用组数据证实了先前报道的通过GWAS / eQTL重叠（例如MLPH）鉴定的PrCa靶基因。有趣的是，HiChIP鉴定了PrCa GWAS变体与众所周知在基于eQTL的方法中未检测到的前列腺癌生物学（例如AR）中起作用的基因之间的联系。我们通过对LNCaP细胞系中NKX3-1和AR的变体包含调控元件的CRISPR干扰（CRISPRi）扰动来验证这些发现。我们的结果表明，循环数据除eQTL之外还包含其他信息，并扩大了可与候选易感基因链接的PrCa GWAS基因座的数量。我们通过对LNCaP细胞系中NKX3-1和AR的变体包含调控元件的CRISPR干扰（CRISPRi）扰动来验证这些发现。我们的结果表明，循环数据除eQTL之外还包含其他信息，并扩大了可与候选易感基因链接的PrCa GWAS基因座的数量。我们通过对LNCaP细胞系中NKX3-1和AR的变体包含调控元件的CRISPR干扰（CRISPRi）扰动来验证这些发现。我们的结果表明，循环数据除eQTL之外还包含其他信息，并扩大了可与候选易感基因链接的PrCa GWAS基因座的数量。