{"doi":"10.1101/2023.08.09.23293896","title":"Epigenome-wide association study of incident type 2 diabetes in Black and White participants from the Atherosclerosis Risk in Communities Study","abstract":"ABSTRACT DNA methylation studies of incident type 2 diabetes in US populations are limited, and to our knowledge none included individuals of African descent living in the US. We performed an epigenome-wide association analysis of blood-based methylation levels at CpG sites with incident type 2 diabetes using Cox regression in 2,091 Black and 1,029 White individuals from the Atherosclerosis Risk in Communities study. At an epigenome-wide significance threshold of 10 −7 , we detected 7 novel diabetes-associated CpG sites in C1orf151 (cg05380846: HR= 0.89, p = 8.4 × 10 −12 ), ZNF2 (cg01585592: HR= 0.88, p = 1.6 × 10 −9 ), JPH3 (cg16696007: HR= 0.87, p = 7.8 × 10 −9 ), GPX6 (cg02793507: HR= 0.85, p = 2.7 × 10 −8 and cg00647063: HR= 1.20, p = 2.5 × 10 −8 ), chr17q25 (cg16865890: HR= 0.8, p = 6.9 × 10 −8 ), and chr11p15 (cg13738793: HR= 1.11, p = 7.7 × 10 −8 ). The CpG sites at C1orf151 , ZNF2, JPH3 and GPX6 , were identified in Black adults, chr17q25 was identified in White adults, and chr11p15 was identified upon meta-analyzing the two groups. The CpG sites at JPH3 and GPX6 were likely associated with incident type 2 diabetes independent of BMI. All the CpG sites, except at JPH3 , were likely consequences of elevated glucose at baseline. We additionally replicated known type 2 diabetes-associated CpG sites including cg19693031 at TXNIP , cg00574958 at CPT1A , cg16567056 at PLBC2 , cg11024682 at SREBF1 , cg08857797 at VPS25 , and cg06500161 at ABCG1 , 3 of which were replicated in Black adults at the epigenome-wide threshold. We observed modest increase in type 2 diabetes variance explained upon addition of the significantly associated CpG sites to a Cox model that included traditional type 2 diabetes risk factors and fasting glucose (increase from 26.2% to 30.5% in Black adults; increase from 36.9% to 39.4% in White adults). We examined if groups of proximal CpG sites were associated with incident type 2 diabetes using a gene-region specific and a gene-region agnostic differentially methylated region (DMR) analysis. Our DMR analyses revealed several clusters of significant CpG sites, including a DMR consisting of a previously discovered CpG site at ADCY7 and promoter regions of TP63 which were differentially methylated across all race groups. This study illustrates improved discovery of CpG sites/regions by leveraging both individual CpG site and DMR analyses in an unexplored population. Our findings include genes linked to diabetes in experimental studies (e.g., GPX6 , JPH3, and TP63 ), and future gene-specific methylation studies could elucidate the link between genes, environment, and methylation in the pathogenesis of type 2 diabetes.","journal":"medRxiv","year":2023,"id":393528,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.6171,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":25001,"name":"James S. Pankow","orcid":"0000-0001-7076-483X","position":1,"is_corresponding":false},{"id":245381,"name":"Eric Boerwinkle","orcid":"0000-0001-8813-0544","position":2,"is_corresponding":false},{"id":17640,"name":"Myriam Fornage","orcid":"0000-0003-0677-8158","position":3,"is_corresponding":false},{"id":266269,"name":"Elizabeth Selvin","orcid":"0000-0001-6923-7151","position":4,"is_corresponding":false},{"id":243113,"name":"Debashree Ray","orcid":"0000-0002-0979-2935","position":5,"is_corresponding":false},{"id":662745,"name":"Sowmya Venkataraghavan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T01:19:05.913428Z","pmid":"37609313","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":[]}