Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance.

Autor: Wang QS; Department of Genome Informatics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. qingbow@m.u-tokyo.ac.jp.; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan. qingbow@m.u-tokyo.ac.jp., Hasegawa T; M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan., Namkoong H; Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan. hounamugun@keio.jp., Saiki R; Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan., Edahiro R; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan., Sonehara K; Department of Genome Informatics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan., Tanaka H; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan., Azekawa S; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan., Chubachi S; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan., Takahashi Y; Faculty of Medicine, Osaka University, Suita, Japan., Sakaue S; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.; Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Namba S; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan., Yamamoto K; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.; Laboratory of Children's Health and Genetics, Division of Health Science, Osaka University Graduate School of Medicine, Suita, Japan.; Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan., Shiraishi Y; Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan., Chiba K; Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan., Tanaka H; M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan., Makishima H; Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan., Nannya Y; Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan., Zhang Z; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan., Tsujikawa R; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan., Koike R; Health Science Research and Development Center (HeRD), Tokyo Medical and Dental University, Tokyo, Japan., Takano T; Laboratory of Veterinary Infectious Disease, Department of Veterinary Medicine, Kitasato University, Tokyo, Japan., Ishii M; Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan., Kimura A; Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan., Inoue F; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan., Kanai T; Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan., Fukunaga K; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan., Ogawa S; Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan., Imoto S; Division of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, University of Tokyo, Tokyo, Japan., Miyano S; M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan., Okada Y; Department of Genome Informatics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. yuki-okada@m.u-tokyo.ac.jp.; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. yuki-okada@m.u-tokyo.ac.jp.; Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.; Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2024 Oct; Vol. 56 (10), pp. 2054-2067. Date of Electronic Publication: 2024 Sep 24.
DOI: 10.1038/s41588-024-01896-3
Abstrakt: Studying the genetic regulation of protein expression (through protein quantitative trait loci (pQTLs)) offers a deeper understanding of regulatory variants uncharacterized by mRNA expression regulation (expression QTLs (eQTLs)) studies. Here we report cis-eQTL and cis-pQTL statistical fine-mapping from 1,405 genotyped samples with blood mRNA and 2,932 plasma samples of protein expression, as part of the Japan COVID-19 Task Force (JCTF). Fine-mapped eQTLs (n = 3,464) were enriched for 932 variants validated with a massively parallel reporter assay. Fine-mapped pQTLs (n = 582) were enriched for missense variations on structured and extracellular domains, although the possibility of epitope-binding artifacts remains. Trans-eQTL and trans-pQTL analysis highlighted associations of class I HLA allele variation with KIR genes. We contrast the multi-tissue origin of plasma protein with blood mRNA, contributing to the limited colocalization level, distinct regulatory mechanisms and trait relevance of eQTLs and pQTLs. We report a negative correlation between ABO mRNA and protein expression because of linkage disequilibrium between distinct nearby eQTLs and pQTLs.
(© 2024. The Author(s).)
Databáze: MEDLINE
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