{"doi":"10.1101/2021.08.03.454513","title":"Functional non-coding SNPs in human endothelial cells fine-map vascular trait associations","abstract":"Abstract Functional consequences of genetic variation in the non-coding human genome are difficult to ascertain despite demonstrated associations to common, complex disease traits. To elucidate properties of functional non-coding SNPs with effects in human endothelial cells (EC), we utilized molecular Quantitative Trait Locus (molQTL) analysis for transcription factor binding, chromatin accessibility, and H3K27 acetylation to nominate a set of likely functional non-coding SNPs. Together with information from genome-wide association studies for vascular disease traits, we tested the ability of 34,344 variants to perturb enhancer function in ECs using the highly multiplexed STARR-seq assay. Of these, 5,592 variants validated, whose enriched attributes included: 1) mutations to TF binding motifs for ETS or AP1 that are regulators of EC state, 2) location in accessible and H3K27ac-marked EC chromatin, and 3) molQTLs associations whereby alleles associate with differences in chromatin accessibility and TF binding across genetically diverse ECs. Next, using pro-inflammatory IL1B as an activator of cell state, we observed robust evidence (>50%) of context-specific SNP effects, underscoring the prevalence of non-coding gene-by-environment (GxE) effects. Lastly, using these cumulative data, we fine-mapped vascular disease loci and highlight evidence suggesting mechanisms by which non-coding SNPs at two loci affect risk for Pulse Pressure/Large Artery Stroke, and Abdominal Aortic Aneurysm through respective effects on transcriptional regulation of POU4F1 and LDAH . Together, we highlight the attributes and context dependence of functional non-coding SNPs, and provide new mechanisms underlying vascular disease risk.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":225990,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9291,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":236708,"name":"Lindsey K. Stolze","orcid":"0000-0003-2269-769X","position":1,"is_corresponding":false},{"id":56925,"name":"Tiit Örd","orcid":"0000-0002-3098-1749","position":2,"is_corresponding":false},{"id":348226,"name":"Michael B. Whalen","orcid":"0000-0001-7300-8511","position":3,"is_corresponding":false},{"id":829033,"name":"Paula Martí Torrell","orcid":null,"position":4,"is_corresponding":false},{"id":80484,"name":"Verena M. Link","orcid":"0000-0002-3207-312X","position":5,"is_corresponding":false},{"id":5694,"name":"Minna Kaikkonen-Määttä","orcid":"0000-0001-6294-0979","position":6,"is_corresponding":false},{"id":236709,"name":"Casey E. Romanoski","orcid":"0000-0002-0149-225X","position":7,"is_corresponding":false},{"id":56926,"name":"Anu Toropainen","orcid":"0000-0001-9292-5147","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:30.292454Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}