{"doi":"10.1101/2022.10.19.512814","title":"<i>cis</i>\n                  -eQTL mapping of TB-T2D comorbidity elucidates the involvement of African ancestry in TB susceptibility","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  The validation of genome-wide association signals for tuberculosis (TB) susceptibility and the development of type 2 diabetes (T2D) across diverse populations remain problematic. The ancestry-specific variants (coding and non-coding) that contribute to previously identified differentially expressed genes (DEG) in patients with TB, T2D and comorbid TB-T2D, remain unknown. Identifying ancestry-specific expression quantitative trait loci (eQTLs) can aid in distinguishing the most probable disease-causing variants for population-specific therapeutic interventions. Therefore, this study conducted\n                  <jats:italic>cis</jats:italic>\n                  -eQTL mapping in TB, T2D and TB-T2D patients to identify variants associated with DEG. Both genotyping (Infinium H3A array with ∼2.3 M markers) and RNA sequencing data of 96 complex multi-way admixed South Africans were used for this purpose. Importantly, both global-and local ancestry adjustment were included in statistical analysis to account for complex admixture. Unique gene-variant pairs were associated with TB-T2D on chromosome 7p22 whilst adjusting for Bantu-speaking African ancestry (\n                  <jats:italic>PRKAR1B</jats:italic>\n                  :rs4464850; P=7.68e-07) and Khoe-San ancestry (\n                  <jats:italic>PRKAR1B:</jats:italic>\n                  rs117842122; P=3.66e-07). In addition,\n                  <jats:italic>IFITM3</jats:italic>\n                  (a biomarker for the development of TB) was associated with three SNPs (rs11025530, rs3808990, and rs10896664) on chromosome 11p15 while adjusting for Khoe-San ancestry. Our results also indicated that the upregulation of the\n                  <jats:italic>NLRP6</jats:italic>\n                  inflammasome is strongly associated with people with TB-T2D while adjusting for Khoe-San ancestry. Three African-specific eGenes (\n                  <jats:italic>NLRP6, IFITM3</jats:italic>\n                  and\n                  <jats:italic>PRKAR1B</jats:italic>\n                  ) would have been missed if local ancestry adjustment was not conducted. This study determined a list of ancestry-specific eQTLs in TB-T2D patients that could potentially guide the search for new therapeutic targets for TB-T2D in African populations.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>Author Summary</jats:title>\n                  <jats:p>\n                    The limitation of genome-wide association study (GWAS) is that the particular biological pathway impacted by a variant might not be evident. eQTL mapping can be conducted to determine the impact that a genetic variant might have on the expression of a specific gene in a biological pathway. In this study the use of\n                    <jats:italic>cis</jats:italic>\n                    -eQTL mapping was explored to elucidate the underlying genetic variants that regulate gene expression between TB-T2D and T2D patients, and between TB patients and healthy controls with multi-way genetic admixture from South Africa. Using RNA sequencing data and newly genotyped dataset of 96 individuals (Illumina Infinium H3Africa array with ∼2.5 M markers), we were able to identify ancestry-specific eQTLs. eQTLs of indigenous Khoe-San ancestral origin were identified in genetic regions previously implicated in TB and T2D in African populations. If local ancestry was not incorporated in the\n                    <jats:italic>cis</jats:italic>\n                    -eQTL mapping analysis these important African-specific eQTLs would have been missed. Our results provide a list of possible ancestry-specific causal variants associated with TB-T2 comorbidity that could guide the search for new therapeutic targets for African-specific populations. Including populations with complex ancestry and admixture in genetic studies is necessary to improve the quality of genetic research in sub-Saharan African groups.\n                  </jats:p>\n                </jats:sec>","journal":null,"year":null,"id":593144,"datarank":0.3952360136168072,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.035551722697051515,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.035551722697051515,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":3,"citers_with_citation_signal":2,"citers_with_endowment":2,"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":759770,"name":"Caitlin Uren","orcid":"0000-0003-2358-0135","position":1,"is_corresponding":false},{"id":419177,"name":"Clare Eckold","orcid":null,"position":2,"is_corresponding":false},{"id":1518103,"name":"Jacqueline M Cliff","orcid":null,"position":3,"is_corresponding":false},{"id":1518104,"name":"Stephanus T Malherbe","orcid":null,"position":4,"is_corresponding":false},{"id":354422,"name":"Katharina Ronacher","orcid":"0000-0002-6371-1462","position":5,"is_corresponding":false},{"id":1161585,"name":"Vinod Kumar","orcid":"0000-0002-7197-7666","position":6,"is_corresponding":false},{"id":33033,"name":"Cisca Wijmenga","orcid":"0000-0002-5635-1614","position":7,"is_corresponding":false},{"id":1379273,"name":"Hazel M Dockrell","orcid":null,"position":8,"is_corresponding":false},{"id":229196,"name":"Reinout van Crevel","orcid":null,"position":9,"is_corresponding":false},{"id":252305,"name":"Gerhard Walzl","orcid":"0000-0003-2487-125X","position":10,"is_corresponding":false},{"id":252318,"name":"Léanie Kleynhans","orcid":"0000-0003-1635-253X","position":11,"is_corresponding":false},{"id":457018,"name":"Marlo Möller","orcid":"0000-0002-0805-6741","position":12,"is_corresponding":false},{"id":1452714,"name":"Yolandi Swart","orcid":"0000-0002-9840-3646","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"<i>cis</i>\n                  -eQTL mapping of TB-T2D comorbidity elucidates the involvement of African ancestry in TB susceptibility","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  The validation of genome-wide association signals for tuberculosis (TB) susceptibility and the development of type 2 diabetes (T2D) across diverse populations remain problematic. The ancestry-specific variants (coding and non-coding) that contribute to previously identified differentially expressed genes (DEG) in patients with TB, T2D and comorbid TB-T2D, remain unknown. Identifying ancestry-specific expression quantitative trait loci (eQTLs) can aid in distinguishing the most probable disease-causing variants for population-specific therapeutic interventions. Therefore, this study conducted\n                  <jats:italic>cis</jats:italic>\n                  -eQTL mapping in TB, T2D and TB-T2D patients to identify variants associated with DEG. Both genotyping (Infinium H3A array with ∼2.3 M markers) and RNA sequencing data of 96 complex multi-way admixed South Africans were used for this purpose. Importantly, both global-and local ancestry adjustment were included in statistical analysis to account for complex admixture. Unique gene-variant pairs were associated with TB-T2D on chromosome 7p22 whilst adjusting for Bantu-speaking African ancestry (\n                  <jats:italic>PRKAR1B</jats:italic>\n                  :rs4464850; P=7.68e-07) and Khoe-San ancestry (\n                  <jats:italic>PRKAR1B:</jats:italic>\n                  rs117842122; P=3.66e-07). In addition,\n                  <jats:italic>IFITM3</jats:italic>\n                  (a biomarker for the development of TB) was associated with three SNPs (rs11025530, rs3808990, and rs10896664) on chromosome 11p15 while adjusting for Khoe-San ancestry. Our results also indicated that the upregulation of the\n                  <jats:italic>NLRP6</jats:italic>\n                  inflammasome is strongly associated with people with TB-T2D while adjusting for Khoe-San ancestry. Three African-specific eGenes (\n                  <jats:italic>NLRP6, IFITM3</jats:italic>\n                  and\n                  <jats:italic>PRKAR1B</jats:italic>\n                  ) would have been missed if local ancestry adjustment was not conducted. This study determined a list of ancestry-specific eQTLs in TB-T2D patients that could potentially guide the search for new therapeutic targets for TB-T2D in African populations.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>Author Summary</jats:title>\n                  <jats:p>\n                    The limitation of genome-wide association study (GWAS) is that the particular biological pathway impacted by a variant might not be evident. eQTL mapping can be conducted to determine the impact that a genetic variant might have on the expression of a specific gene in a biological pathway. In this study the use of\n                    <jats:italic>cis</jats:italic>\n                    -eQTL mapping was explored to elucidate the underlying genetic variants that regulate gene expression between TB-T2D and T2D patients, and between TB patients and healthy controls with multi-way genetic admixture from South Africa. Using RNA sequencing data and newly genotyped dataset of 96 individuals (Illumina Infinium H3Africa array with ∼2.5 M markers), we were able to identify ancestry-specific eQTLs. eQTLs of indigenous Khoe-San ancestral origin were identified in genetic regions previously implicated in TB and T2D in African populations. If local ancestry was not incorporated in the\n                    <jats:italic>cis</jats:italic>\n                    -eQTL mapping analysis these important African-specific eQTLs would have been missed. Our results provide a list of possible ancestry-specific causal variants associated with TB-T2 comorbidity that could guide the search for new therapeutic targets for African-specific populations. Including populations with complex ancestry and admixture in genetic studies is necessary to improve the quality of genetic research in sub-Saharan African groups.\n                  </jats:p>\n                </jats:sec>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"26657633","pmcid":null,"openalex_id":null,"authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"cc-by","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2022/10/19/2022.10.19.512814.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2022.10.19.512814","host_type":"publisher"}],"fields_of_study":[],"mesh_terms":[],"keywords":[],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"refsnp"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-26T17:26:50.888588Z","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":[]}