Trans-eQTL mapping prioritises USP18 as a negative regulator of interferon response at a lupus risk locus

作者：Krista Freimann, Anneke Brümmer, Robert Warmerdam, Tarran S. Rupall, Ana Laura Hernández-Ledesma, Joshua Chiou, Emily Holzinger, Joseph Maranville, Nikolina Nakić, Halit Ongen, Luca Stefanucci, Michael C. Turchin, eQTLGen, Habibul Ahsan, Philip Awadalla, Alexis Battle, Frank Beutner, Cornelis Blauwendraat, Collins K. Boahen, Toni Boltz, Marc Jan Bonder, Dorret I. Boomsma, John Budde, Katie L. Burnham, John C. Chambers, Evans K. Cheruiyot, Surya B. Chhetri, Annique Claringbould, Carlos Cruchaga, Kensuke Daida, Emma E. Davenport, Patrick Deelen, Devin Dikec, Diptavo Dutta, Tõnu Esko, R. Farhad, Aiman Farzeen, Marie-Julie Favé, Luigi Ferrucci, Timothy M. Frayling, Koichi Fukunaga, J. Raphael Gibbs, Greg Gibson, Christian Gieger, Priyanka Gorijala, Marleen M. J. van Greevenbroek, Binisha H. Mishra, Takanori Hasegawa, Jouke Jan Hottenga, Mashta Ikram, Michael Inouye, Rick Jansen, Farzana Jasmine, Matt Johnson, Mika Kähönen, Muhammad G. Kibriya, Holger Kirsten, Julian C. Knight, Péter Kovács, Knut Krohn, Viktorija Kukushkina, Vinod Kumar, Sandra Lapinska, Terho Lehtimäki, Yun Li, Markus Loeffler, Marie Loh, Leo-Pekka Lyytikäinen, Reedik Mägi, Javier Martı́n, Ángel Martínez-Pérez, Allan F. McRae, Joyce van Meurs, Lili Milani, Pashupati P. Mishra, Younes Mokrab, Grant W. Montgomery, Juha Mykkänen, Haroon Naeem, Sini Nagpal, Ho Namkoong, Matthias Nauck, Yukinori Okada, Roel Ophoff, Katja Pahkala, Bogdan Paşaniuc, Dirk S. Paul, Brenda W.J.H. Penninx, Elodie Persyn, Annette Peters, Brandon L. Pierce, René Pool, Holger Prokisch, Laura M. Raffield, Venket Raghavan, Olli T. Raitakari, Emma Raitoharju, María Rivas-Torrubia, Ruth D. Rodríguez, Suvi P. Rovio, Jessie Sanford, Markus Scholz, Andrew Singleton, P. Eline Slagboom, José Manuel Soria, Juan Carlos Souto, Michael Stümvoll, Yun Ju Sung, Darwin Tay, Alexander Teumer, Joachim Thiery, Alex Tokolyi, Tong Lin, Anke Tönjes, Jan H. Veldink, Joost Verlouw, Peter M. Visscher, Uwe Völker, Qingbo S. Wang, Stefan Weiß, Jia Wen, Harm-Jan Westra, Andrew R. Wood, Manke Xie, Dasha V. Zhernakova, DIRECT Brown, Andrew Brown, Théo Dupuis, Ana Viñuela, Marta E. Alarcón‐Riquelme, Guillermo Barturen, Lude Franke, Urmo Võsa, Carla P. Jones, Alejandra Medina-Rivera, Gosia Trynka, Kai Kisand, Sven Bergmann, Kaur Alasoo · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-63856-7 · 被引用次数：7 · 研究领域：Systemic Lupus Erythematosus Research、interferon and immune responses、Cancer-related molecular mechanisms research

Although genome-wide association studies have provided valuable insights into the genetic basis of complex traits and diseases, translating these findings to causal genes and their downstream mechanisms remains challenging. We performed trans expression quantitative trait locus (trans-eQTL) meta-analysis in 3734 lymphoblastoid cell line samples, identifying four robust loci that replicated in an independent multi-ethnic dataset of 682 individuals. The trans-eQTL signal at the ubiquitin specific peptidase 18 (USP18) locus colocalised with a GWAS signal for systemic lupus erythematosus (SLE). USP18 is a known negative regulator of interferon signalling and the SLE risk allele increased the expression of 50 interferon-inducible genes, suggesting that the risk allele impairs USP18's ability to effectively limit the interferon response. Intriguingly, the USP18 trans-eQTL signal would not have been discovered in a meta-analysis of up to 43,301 whole blood samples, reaffirming the importance of capturing context-specific genetic effects for GWAS interpretation.