{"doi":"10.3390/cancers16112072","title":"Characterizing the Relationship between Expression Quantitative Trait Loci (eQTLs), DNA Methylation Quantitative Trait Loci (mQTLs), and Breast Cancer Risk Variants","abstract":"Purpose: To assess the association of a polygenic risk score (PRS) for functional genetic variants with the risk of developing breast cancer. Methods: Summary data-based Mendelian randomization (SMR) and heterogeneity in dependent instruments (HEIDI) were used to identify breast cancer risk variants associated with gene expression and DNA methylation levels. A new SMR-based PRS was computed from the identified variants (functional PRS) and compared to an established 313-variant breast cancer PRS (GWAS PRS). The two scores were evaluated in 3560 breast cancer cases and 3383 non-cancer controls and also in a prospective study (n = 10,213) comprising 418 cases. Results: We identified 149 variants showing pleiotropic association with breast cancer risk (eQTLHEIDI > 0.05 = 9, mQTLHEIDI > 0.05 = 165). The discriminatory ability of the functional PRS (AUCcontinuous [95% CI]: 0.540 [0.526 to 0.553]) was found to be lower than that of the GWAS PRS (AUCcontinuous [95% CI]: 0.609 [0.596 to 0.622]). Even when utilizing 457 distinct variants from both the functional and GWAS PRS, the combined discriminatory performance remained below that of the GWAS PRS (AUCcontinuous, combined [95% CI]: 0.561 [0.548 to 0.575]). A binary high/low-risk classification based on the 80th centile PRS in controls revealed a 6% increase in cases using the GWAS PRS compared to the functional PRS. The functional PRS identified an additional 12% of high-risk cases but also led to a 13% increase in high-risk classification among controls. Similar findings were observed in the SCHS prospective cohort, where the GWAS PRS outperformed the functional PRS, and the highest-performing PRS, a combined model, did not significantly improve over the GWAS PRS. Conclusions: While this study identified potentially functional variants associated with breast cancer risk, their inclusion did not substantially enhance the predictive accuracy of the GWAS PRS.","journal":"Cancers","year":2024,"id":476866,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.894,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1026422,"name":"Alexis Jiaying Khng","orcid":"0000-0003-1004-6048","position":1,"is_corresponding":false},{"id":14107,"name":"Benita Kiat Tee Tan","orcid":"0000-0002-8573-4606","position":2,"is_corresponding":false},{"id":90169,"name":"Chiea Chuen Khor","orcid":"0000-0002-1128-4729","position":3,"is_corresponding":false},{"id":259993,"name":"Ern Yu Tan","orcid":"0000-0001-7726-3974","position":4,"is_corresponding":false},{"id":260000,"name":"Geok Hoon Lim","orcid":"0000-0002-5296-3437","position":5,"is_corresponding":false},{"id":341681,"name":"Jian‐Min Yuan","orcid":"0000-0002-4620-3108","position":6,"is_corresponding":false},{"id":1314762,"name":"Su‐Ming Tan","orcid":null,"position":7,"is_corresponding":false},{"id":236702,"name":"Xuling Chang","orcid":"0000-0001-7471-4768","position":8,"is_corresponding":false},{"id":1026420,"name":"Veronique Kiak Mien Tan","orcid":"0000-0001-8493-8191","position":9,"is_corresponding":false},{"id":240625,"name":"Xueling Sim","orcid":"0000-0002-1233-7642","position":10,"is_corresponding":false},{"id":390744,"name":"Rajkumar Dorajoo","orcid":"0000-0001-6608-2051","position":11,"is_corresponding":false},{"id":260003,"name":"Woon‐Puay Koh","orcid":"0000-0002-5674-6341","position":12,"is_corresponding":false},{"id":260013,"name":"Mikael Hartman","orcid":"0000-0001-5726-9965","position":13,"is_corresponding":false},{"id":31517,"name":"Jingmei Li","orcid":"0000-0001-8587-7511","position":14,"is_corresponding":false},{"id":259986,"name":"Peh Joo Ho","orcid":"0000-0002-3017-4023","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:06:29.605760Z","pmid":"38893190","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":[]}