Duan, Yuan-YuanChen, Xiao-FengZhu, Ren-JieJia, Ying-YingHuang, Xiao-TingZhang, MengYang, NingDong, Shan-ShanZeng, MengqiFeng, ZhihuiZhu, Dong-LiWu, HaoJiang, FengShi, WeiHu, Wei-XinKe, XinChen, HaoLiu, YunlongJing, Rui-HuaGuo, YanLi, MengYang, Tie-Lin2024-06-122024-06-122023Duan 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.2023.07.002https://hdl.handle.net/1805/41492Most 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.en-USPublisher PolicyInsulin resistanceGWASNoncoding SNPsSTARR-seqBiased allelic enhancer activity effectIRS1rs952227Genetic regulatory mechanismsArticle