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<p>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 <i>trans</i> expression quantitative trait locus (<i>trans</i>-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 <i>trans</i>-eQTL signal at the ubiquitin specific peptidase 18 (<i>USP18)</i> 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 <i>USP18 trans</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月2日

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  • Krista Freimann,
  • Anneke Brümmer,
  • Robert Warmerdam,
  • Tarran S. Rupall,
  • Ana Laura Hernández-Ledesma,
  • Joshua Chiou,
  • Emily R. Holzinger,
  • Joseph C. Maranville,
  • Nikolina Nakic,
  • Halit Ongen,
  • Luca Stefanucci,
  • Michael C. Turchin,
  • eQTLGen,
  • Habibul Ahsan,
  • Philip Awadalla,
  • Alexis Battle,
  • Frank Beutner,
  • Cornelis Blauwendraat,
  • Collins Boahen,
  • Toni Boltz,
  • Marc Jan Bonder,
  • Dorret I. Boomsma,
  • John Budde,
  • Katie L. Burnham,
  • John Chambers,
  • Evans Cheruiyot,
  • Surya B. Chhetri,
  • Annique Claringbould,
  • Carlos Cruchaga,
  • Kensuke Daida,
  • Emma E. Davenport,
  • Patrick Deelen,
  • Devin Dikec,
  • Diptavo Dutta,
  • Tõnu Esko,
  • Radi Farhad,
  • Aiman Farzeen,
  • Marie-Julie Favé,
  • Luigi Ferrucci,
  • Timothy M. Frayling,
  • Koichi Fukunaga,
  • J. Raphael Gibbs,
  • Greg Gibson,
  • Christian Gieger,
  • Priyanka Gorijala,
  • Marleen van Greevenbroek,
  • Binisha Hamal Mishra,
  • Takanori Hasegawa,
  • Jouke Jan Hottenga,
  • M. Arfan Ikram,
  • Michael Inouye,
  • Rick Jansen,
  • Farzana Jasmine,
  • Matt Johnson,
  • Mika Kähönen,
  • Muhammad Kibriya,
  • Holger Kirsten,
  • Julian C. Knight,
  • Peter Kovacs,
  • Knut Krohn,
  • Viktorija Kukushkina,
  • Vinod Kumar,
  • Sandra Lapinska,
  • Terho Lehtimäki,
  • Yun Li,
  • Markus Loeffler,
  • Marie Loh,
  • Leo-Pekka Lyytikäinen,
  • Reedik Mägi,
  • Javier Martin,
  • Angel Martinez-Perez,
  • 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 Pasaniuc,
  • Dirk S. Paul,
  • Brenda W.J.H Penninx,
  • Elodie Persyn,
  • Annette Peters,
  • Brandon Pierce,
  • René Pool,
  • Holger Prokisch,
  • Laura Raffield,
  • Venket Raghavan,
  • Olli T. Raitakari,
  • Emma Raitoharju,
  • María Rivas-Torrubia,
  • Ruth D. Rodríguez,
  • Suvi P. Rovio,
  • Jessie Sanford,
  • Markus Scholz,
  • Andrew Singleton,
  • Eline Slagboom,
  • José Manuel Soria,
  • Juan Carlos Souto,
  • Michael Stumvoll,
  • Yun Ju Sung,
  • Darwin Tay,
  • Alexander Teumer,
  • Joachim Thiery,
  • Alex Tokolyi,
  • Lin Tong,
  • Anke Tönjes,
  • Jan Veldink,
  • Joost Verlouw,
  • Peter M. Visscher,
  • Uwe Völker,
  • Qingbo S. Wang,
  • Stefan Weiss,
  • Jia Wen,
  • Harm-Jan Westra,
  • Andrew R. Wood,
  • Manke Xie,
  • Dasha Zhernakova,
  • DIRECT Brown,
  • Andrew Brown,
  • Théo Dupuis,
  • Ana Viñuela,
  • PRECISESADS Clinical Consortium,
  • Marta E. Alarcón-Riquelme,
  • Guillermo Barturen,
  • Lude Franke,
  • Urmo Võsa,
  • Carla P. Jones,
  • Alejandra Medina-Rivera,
  • Gosia Trynka,
  • Kai Kisand,
  • Sven Bergmann,
  • Kaur Alasoo

摘要

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.