High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes
dc.contributor.author | Duan, Yuan-Yuan | |
dc.contributor.author | Chen, Xiao-Feng | |
dc.contributor.author | Zhu, Ren-Jie | |
dc.contributor.author | Jia, Ying-Ying | |
dc.contributor.author | Huang, Xiao-Ting | |
dc.contributor.author | Zhang, Meng | |
dc.contributor.author | Yang, Ning | |
dc.contributor.author | Dong, Shan-Shan | |
dc.contributor.author | Zeng, Mengqi | |
dc.contributor.author | Feng, Zhihui | |
dc.contributor.author | Zhu, Dong-Li | |
dc.contributor.author | Wu, Hao | |
dc.contributor.author | Jiang, Feng | |
dc.contributor.author | Shi, Wei | |
dc.contributor.author | Hu, Wei-Xin | |
dc.contributor.author | Ke, Xin | |
dc.contributor.author | Chen, Hao | |
dc.contributor.author | Liu, Yunlong | |
dc.contributor.author | Jing, Rui-Hua | |
dc.contributor.author | Guo, Yan | |
dc.contributor.author | Li, Meng | |
dc.contributor.author | Yang, Tie-Lin | |
dc.contributor.department | Medical and Molecular Genetics, School of Medicine | |
dc.date.accessioned | 2024-06-12T18:18:01Z | |
dc.date.available | 2024-06-12T18:18:01Z | |
dc.date.issued | 2023 | |
dc.description.abstract | Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes. | |
dc.eprint.version | Final published version | |
dc.identifier.citation | Duan YY, Chen XF, Zhu RJ, et al. High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes. Am J Hum Genet. 2023;110(8):1266-1288. doi:10.1016/j.ajhg.2023.07.002 | |
dc.identifier.uri | https://hdl.handle.net/1805/41492 | |
dc.language.iso | en_US | |
dc.publisher | Elsevier | |
dc.relation.isversionof | 10.1016/j.ajhg.2023.07.002 | |
dc.relation.journal | American Journal of Human Genetics | |
dc.rights | Publisher Policy | |
dc.source | PMC | |
dc.subject | Insulin resistance | |
dc.subject | GWAS | |
dc.subject | Noncoding SNPs | |
dc.subject | STARR-seq | |
dc.subject | Biased allelic enhancer activity effect | |
dc.subject | IRS1 | |
dc.subject | rs952227 | |
dc.subject | Genetic regulatory mechanisms | |
dc.title | High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes | |
dc.type | Article | |
ul.alternative.fulltext | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10432149/ |