Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church Street, Room 4565 NUB, Ann Arbor, MI, 48109-1065, USA.
Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
BMC Biol. 2020 Aug 10;18(1):97. doi: 10.1186/s12915-020-00830-3.
Previous expression quantitative trait loci (eQTL) studies have identified thousands of genetic variants to be associated with gene expression at the mRNA level in the human liver. However, protein expression often correlates poorly with mRNA levels. Thus, protein quantitative trait loci (pQTL) study is required to identify genetic variants that regulate protein expression in human livers.
We conducted a genome-wide pQTL study in 287 normal human liver samples and identified 900 local pQTL variants and 4026 distant pQTL variants. We further discovered 53 genome hotspots of pQTL variants. Transcriptional region mapping analysis showed that 1133 pQTL variants are in transcriptional regulatory regions. Genomic region enrichment analysis of the identified pQTL variants revealed 804 potential regulatory interactions among 595 predicted regulators (e.g., non-coding RNAs) and 394 proteins. Moreover, pQTL variants and trait-variant integration analysis implied several novel mechanisms underlying the relationships between protein expression and liver diseases, such as alcohol dependence. Notably, over 2000 of the identified pQTL variants have not been reported in previous eQTL studies, suggesting extensive involvement of genetic polymorphisms in post-transcriptional regulation of protein expression in human livers.
We have partially established protein expression regulation networks in human livers and generated a wealth of pQTL data that could serve as a valuable resource for the scientific community.
先前的表达数量性状基因座（eQTL）研究已经鉴定出数千个与人类肝脏中 mRNA 水平的基因表达相关的遗传变异。然而，蛋白质表达通常与 mRNA 水平相关性较差。因此，需要进行蛋白质数量性状基因座（pQTL）研究，以鉴定调节人类肝脏中蛋白质表达的遗传变异。
我们在 287 个正常人类肝脏样本中进行了全基因组 pQTL 研究，鉴定出 900 个局部 pQTL 变异和 4026 个远距离 pQTL 变异。我们进一步发现了 53 个 pQTL 变异的基因组热点。转录区域映射分析表明，1133 个 pQTL 变异位于转录调控区域。鉴定出的 pQTL 变异的基因组区域富集分析揭示了 595 个预测调节剂（例如非编码 RNA）和 394 个蛋白质之间的 804 个潜在调节相互作用。此外，pQTL 变异与性状变异综合分析表明，在蛋白质表达与肝脏疾病之间的关系中存在几种新的机制，例如酒精依赖。值得注意的是，在先前的 eQTL 研究中，超过 2000 个鉴定出的 pQTL 变异尚未报道，这表明遗传多态性广泛参与了人类肝脏中蛋白质表达的转录后调控。
我们已经部分建立了人类肝脏中蛋白质表达调控网络，并产生了大量的 pQTL 数据，这些数据可以作为科学界的宝贵资源。
