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In eQTL fine-mapping, the existence of causal variants for gene expression is not guaranteed, since the genetic heritability of gene expression explained by nearby (cis-) variants is limited. Here we introduce a refined fine-mapping algorithm, named Knockoff\u2013Finemap combination (KFc). KFc estimates the probability that the causal variant(s) exist in the cis-window of a gene through construction of knockoff genotypes (i.e. a set of synthetic genotypes that resembles the original genotypes), and uses it to adjust the posterior inclusion probabilities (PIPs). Utilizing simulated gene expression data, we show that KFc results in calibrated PIP distribution with improved precision. When applied to gene expression data of 465 genotyped samples from the Japan COVID-19 Task Force (JCTF), KFc resulted in significant enrichment of a functional score as well as reporter assay hits in the top PIP bins. When combined with functional priors derived from an external fine-mapping study (GTEx), KFc resulted in a significantly higher proportion of hematopoietic trait putative causal variants in the top PIP bins. Our work presents improvements in the precision of a major fine-mapping algorithm.<\/jats:p>","DOI":"10.1093\/nargab\/lqad090","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T08:04:15Z","timestamp":1698739455000},"source":"Crossref","is-referenced-by-count":1,"title":["Estimating gene-level false discovery probability improves eQTL statistical fine-mapping precision"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9110-5830","authenticated-orcid":false,"given":"Qingbo S","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Statistical Genetics, Osaka University Graduate School of Medicine , Suita , 565-0871,\u00a0 Japan"},{"name":"Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University , Suita,\u00a0565-0871,\u00a0 Japan"},{"name":"Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo , Tokyo , 113-0033,\u00a0 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuya","family":"Edahiro","sequence":"additional","affiliation":[{"name":"Department of Statistical Genetics, Osaka University Graduate School of Medicine , Suita , 565-0871,\u00a0 Japan"},{"name":"Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine , Suita,\u00a0565-0871 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6181-4284","authenticated-orcid":false,"given":"Ho","family":"Namkoong","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Keio University School of Medicine , Tokyo,\u00a0160-8582 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takanori","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"M&D Data Science Center, Tokyo Medical and Dental University , Tokyo,\u00a0113-8510 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuya","family":"Shirai","sequence":"additional","affiliation":[{"name":"Department of Statistical Genetics, Osaka University Graduate School of Medicine , Suita , 565-0871,\u00a0 Japan"},{"name":"Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine , Suita,\u00a0565-0871 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyuto","family":"Sonehara","sequence":"additional","affiliation":[{"name":"Department of Statistical Genetics, Osaka University Graduate School of Medicine , Suita , 565-0871,\u00a0 Japan"},{"name":"Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo , Tokyo , 113-0033,\u00a0 Japan"},{"name":"Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University , Suita,\u00a0565-0871 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Japan COVID-19 Task\u00a0Force","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Kumanogoh","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine , Suita,\u00a0565-0871 , Japan"},{"name":"Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University , Suita,\u00a0565-0871 , Japan"},{"name":"Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), Osaka University , Suita,\u00a0565-0871 , Japan"},{"name":"Center for Infectious Disease Education and Research (CiDER), Osaka University , Suita,\u00a0565-0871 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4396-1664","authenticated-orcid":false,"given":"Makoto","family":"Ishii","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Nagoya University Graduate School of Medicine , 65 tsurumai, Showa-ku, Nagoya,\u00a0466-8550 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuji","family":"Koike","sequence":"additional","affiliation":[{"name":"Health Science Research and Development Center (HeRD), Tokyo Medical and Dental University , Tokyo,\u00a0113-8510 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akinori","family":"Kimura","sequence":"additional","affiliation":[{"name":"Institute of Research, Tokyo Medical and Dental University , Tokyo,\u00a0113-8510 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2989-308X","authenticated-orcid":false,"given":"Seiya","family":"Imoto","sequence":"additional","affiliation":[{"name":"Division of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, the University of Tokyo , Tokyo,\u00a0108-8639 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoru","family":"Miyano","sequence":"additional","affiliation":[{"name":"M&D Data Science Center, Tokyo Medical and Dental University , Tokyo,\u00a0113-8510 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7778-5374","authenticated-orcid":false,"given":"Seishi","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Department of Pathology and Tumor Biology, Kyoto University , Kyoto,\u00a0606-8315 , Japan"},{"name":"Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University , Kyoto,\u00a0606-8303 , Japan"},{"name":"Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute , Stockholm,\u00a0171 77 , Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takanori","family":"Kanai","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine , Tokyo,\u00a0160-8582 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Fukunaga","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine , Tokyo,\u00a0160-8582 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0311-8472","authenticated-orcid":false,"given":"Yukinori","family":"Okada","sequence":"additional","affiliation":[{"name":"Department of Statistical Genetics, Osaka University Graduate School of Medicine , Suita , 565-0871,\u00a0 Japan"},{"name":"Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University , Suita,\u00a0565-0871,\u00a0 Japan"},{"name":"Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo , Tokyo , 113-0033,\u00a0 Japan"},{"name":"Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University , Suita,\u00a0565-0871 , Japan"},{"name":"Center for Infectious Disease Education and Research (CiDER), Osaka University , Suita,\u00a0565-0871 , Japan"},{"name":"Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences , Yokohama,\u00a0230-0045 , 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