{"doi":"10.1101/2024.12.19.24319316","title":"Single-cell transcriptome-wide Mendelian randomization and colocalization analyses uncover cell-specific mechanisms in atherosclerotic cardiovascular disease","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>\n                  Genome-wide association studies (GWAS) have identified numerous genetic loci influencing human disease risk. However, linking these loci to causal genes remains challenging, limiting opportunities for drug target discovery. Transcriptome-wide association studies (TWAS) address this by linking variants to gene expression, but typically rely on bulk RNA sequencing, which lacks cell-specific resolution. Here, we present a single-cell TWAS pipeline combining\n                  <jats:italic>cis</jats:italic>\n                  -Mendelian randomization (MR) with colocalization analyses at the single-cell level. As a case study, we examined how genetically proxied gene expression in immune cells influences atherosclerotic cardiovascular disease (ASCVD) risk. We integrated single-cell expression quantitative trait loci (sc-eQTL) for 14 immune cell types with GWAS for coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease. Single-cell\n                  <jats:italic>cis</jats:italic>\n                  -MR analyses revealed 440 gene-outcome associations across cell types, 84% of which were missed by bulk TWAS, despite a considerably smaller sample size of the sc-eQTL dataset. Of these associations, 17 were replicated with external\n                  <jats:italic>cis</jats:italic>\n                  -eQTLs and demonstrated colocalization with ASCVD GWAS signals. Notably, genetically proxied expression of\n                  <jats:italic>LIPA</jats:italic>\n                  in monocytes was associated with coronary artery disease, large artery atherosclerotic stroke, and subclinical atherosclerosis traits. These findings were confirmed in a phenome-wide association study without evidence of associations with unexpected clinical outcomes. Single-cell RNA sequencing and immunohistochemistry of human carotid plaques revealed high\n                  <jats:italic>LIPA</jats:italic>\n                  expression in plaque macrophages. Our pipeline provides a solution for the discovery of cell-specific expression patterns that drive genetic predisposition to human disease, potentially impacting target selection for cell-tailored therapeutics.\n                </jats:p>","journal":null,"year":null,"id":597411,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":748232,"name":"Paulo Vinícius Gil Alabarse","orcid":"0000-0002-9721-9302","position":1,"is_corresponding":false},{"id":302170,"name":"Rainer Malik","orcid":"0000-0001-9212-2520","position":2,"is_corresponding":false},{"id":17609,"name":"Muralidharan Sargurupremraj","orcid":"0000-0003-1684-3750","position":3,"is_corresponding":false},{"id":319653,"name":"Jürgen Bernhagen","orcid":"0000-0003-2996-2652","position":4,"is_corresponding":false},{"id":12191,"name":"Martin Dichgans","orcid":"0000-0002-0654-387X","position":5,"is_corresponding":false},{"id":1525526,"name":"Sebastian-Edgar Baumeister","orcid":null,"position":6,"is_corresponding":false},{"id":625434,"name":"Marios K. Georgakis","orcid":"0000-0003-3507-3659","position":7,"is_corresponding":false},{"id":1284560,"name":"Anushree Ray","orcid":"0009-0000-8890-0975","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Single-cell transcriptome-wide Mendelian randomization and colocalization analyses uncover cell-specific mechanisms in atherosclerotic cardiovascular disease","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>\n                  Genome-wide association studies (GWAS) have identified numerous genetic loci influencing human disease risk. However, linking these loci to causal genes remains challenging, limiting opportunities for drug target discovery. Transcriptome-wide association studies (TWAS) address this by linking variants to gene expression, but typically rely on bulk RNA sequencing, which lacks cell-specific resolution. Here, we present a single-cell TWAS pipeline combining\n                  <jats:italic>cis</jats:italic>\n                  -Mendelian randomization (MR) with colocalization analyses at the single-cell level. As a case study, we examined how genetically proxied gene expression in immune cells influences atherosclerotic cardiovascular disease (ASCVD) risk. We integrated single-cell expression quantitative trait loci (sc-eQTL) for 14 immune cell types with GWAS for coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease. Single-cell\n                  <jats:italic>cis</jats:italic>\n                  -MR analyses revealed 440 gene-outcome associations across cell types, 84% of which were missed by bulk TWAS, despite a considerably smaller sample size of the sc-eQTL dataset. Of these associations, 17 were replicated with external\n                  <jats:italic>cis</jats:italic>\n                  -eQTLs and demonstrated colocalization with ASCVD GWAS signals. Notably, genetically proxied expression of\n                  <jats:italic>LIPA</jats:italic>\n                  in monocytes was associated with coronary artery disease, large artery atherosclerotic stroke, and subclinical atherosclerosis traits. These findings were confirmed in a phenome-wide association study without evidence of associations with unexpected clinical outcomes. Single-cell RNA sequencing and immunohistochemistry of human carotid plaques revealed high\n                  <jats:italic>LIPA</jats:italic>\n                  expression in plaque macrophages. Our pipeline provides a solution for the discovery of cell-specific expression patterns that drive genetic predisposition to human disease, potentially impacting target selection for cell-tailored therapeutics.\n                </jats:p>","is_dataset_classified":null,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23304386","pmcid":null,"openalex_id":"https://openalex.org/W4405729568","authors":[],"funders":[{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"unidentified","title":"unidentified"}],"total_grants":1,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":1},{"year":2026,"count":1}],"oa_status":"green","license":"cc-by-nc","oa_locations":[{"url":"https://www.medrxiv.org/content/medrxiv/early/2024/12/20/2024.12.19.24319316.full.pdf","host_type":"repository"},{"url":"https://www.medrxiv.org/content/medrxiv/early/2024/12/20/2024.12.19.24319316.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2024.12.19.24319316","host_type":"publisher"},{"url":"https://doi.org/10.1101/2024.12.19.24319316","host_type":"repository"},{"url":"https://pub.dzne.de/record/279452","host_type":"repository"},{"url":"https://pub.dzne.de/record/279452/files/DZNE-2025-00779.pdf","host_type":"repository"},{"url":"https://doi.org/10.1016/j.ajhg.2025.06.001","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/40555237","host_type":""},{"url":"http://dx.doi.org/10.1016/j.ajhg.2025.06.001","host_type":""},{"url":"https://epub.ub.uni-muenchen.de/128269/","host_type":""}],"fields_of_study":["Single-cell and spatial transcriptomics","Genetic Associations and Epidemiology","Atherosclerosis and Cardiovascular Diseases","0301 basic medicine","03 medical and health sciences"],"mesh_terms":[],"keywords":["Mendelian randomization","Genome-wide association study","Expression quantitative trait loci","Transcriptome","Biology","Disease","Genetic association","Candidate gene","Genetics","Gene expression","Gene","Single-nucleotide polymorphism","Medicine","Internal medicine","Genotype","Genetic variants","Transcriptome: genetics","Quantitative Trait Loci","Coronary Artery Disease","Polymorphism, Single Nucleotide","drug target","Article","immune cells","Mendelian Randomization Analysis: methods","cardiovascular disease","Humans","colocalization analysis","Genetic Predisposition to Disease","Cardiovascular Diseases: genetics","info:eu-repo/classification/ddc/570","Quantitative Trait Loci: genetics","Atherosclerosis: genetics","RNA sequencing","Mendelian Randomization Analysis","Atherosclerosis","Single-Cell Analysis: methods","Cardiovascular Diseases","Atherosclerosis: pathology","Single-Cell Analysis","Polymorphism, Single Nucleotide: genetics","Coronary Artery Disease: genetics"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-28T13:10:36.076147Z","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":[]}