Trans-eQTL mapping prioritises USP18 as a negative regulator of interferon response at a lupus risk locus
Abstract
Abstract 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.
Article Details
Authors (140)
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
Division of Endocrinology, Nephrology and Rheumatology, Department of Medicine III, Leipzig University
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. Rodriguez
Suvi P. Rovio
Jessie Sanford
Markus Scholz
Andrew Singleton
Eline Slagboom
José Manuel Soria
Juan Carlos Souto
Michael Stumvoll
Yun Ju Sung
Washington University in St. Louis, St. Louis, MO, USA.
Darwin Tay
Alexander Teumer
Joachim Thiery
Alex Tokolyi
Lin Tong
Radiology Intervention Department, Shanghai Putuo District Liqun Hospital, Shanghai
Anke Tönjes
Jan Veldink
Joost Verlouw
Peter M. Visscher
Uwe Völker
Department of Functional Genomics, Universitätsmedizin Greifswald, Greifswald, Germany
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