{"doi":"10.1101/2023.10.20.23297214","title":"Ancestry-specific regulatory and disease architectures are likely due to cell-type-specific gene-by-environment interactions","abstract":"Abstract Multi-ancestry genome-wide association studies (GWAS) have highlighted the existence of variants with ancestry-specific effect sizes. Understanding where and why these ancestry-specific effects occur is fundamental to understanding the genetic basis of human diseases and complex traits. Here, we characterized genes differentially expressed across ancestries (ancDE genes) at the cell-type level by leveraging single-cell RNA-seq data in peripheral blood mononuclear cells for 21 individuals with East Asian (EAS) ancestry and 23 individuals with European (EUR) ancestry (172K cells); then, we tested if variants surrounding those genes were enriched in disease variants with ancestry-specific effect sizes by leveraging ancestry-matched GWAS of 31 diseases and complex traits (average N = 90K and 267K in EAS and EUR, respectively). We observed that ancDE genes tend to be cell-type-specific, to be enriched in genes interacting with the environment, and in variants with ancestry-specific disease effect sizes, suggesting the impact of shared cell-type-specific gene-by-environment (GxE) interactions between regulatory and disease architectures. Finally, we illustrated how GxE interactions might have led to ancestry-specific MCL1 expression in B cells, and ancestry-specific allele effect sizes in lymphocyte count GWAS for variants surrounding MCL1 . Our results imply that large single-cell and GWAS datasets in diverse populations are required to improve our understanding on the effect of genetic variants on human diseases.","journal":"medRxiv","year":2023,"id":392681,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9504,"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":558848,"name":"Steven Gazal","orcid":"0000-0001-5714-7597","position":1,"is_corresponding":false},{"id":1166679,"name":"Juehan Wang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T01:18:56.730121Z","pmid":"37905038","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":[]}