USP18 modulates lupus risk via negative regulation of interferon response

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 3,734 lymphoblastoid cell line samples, identifying four robust loci that replicated in an independent multi-ethnic dataset of 682 individuals. One of these loci was a missense variant in the ubiquitin specific peptidase 18 ( USP18 ) gene that is a known negative regulator of interferon signalling and has previously been associated with increased risk of systemic lupus erythematosus (SLE). In our analysis, 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, most trans -eQTL targets of USP18 lacked independent cis associations with SLE, cautioning against the use of trans -eQTL evidence alone for causal gene prioritisation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement K.F and L.S. were supported by a grant from Open Targets (grant no. OTAR2069). K.A was supported by the Estonian Research Council (grant no. PSG415). K.A. also received funding from the European Union's Horizon 2020 research and innovation program (grant no. 825775). GT, CPJ and TSR were supported by Open Targets (grant no. OTAR2064) and the Wellcome Grant (ref. 220540/Z/20/A, Wellcome Sanger Institute Quinquennial Review 2021-2026). SB was supported by the Swiss National Science Foundation (grant no. 310030_152724/1). K.K. was supported by the Estonian Research Council (grant no. PRG1117). AMR was supported by CONACYT-FORDECYT-PRONACES grant no. [11311] and Programa de Apoyo a Proyectos de Investigacoin e Innovacion Tecnologica-Universidad Nacional Autonoma de Mexico (PAPIIT-UNAM) IN218023. ALHL is a doctoral student from Programa de Doctorado en Ciencias Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), and she receives fellowship 790972 from Consejo Nacional de Humanidades, Ciencias y Tecnologias CONAHCYT, Mexico. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. This publication is the work of the authors and they will serve as guarantors for the contents of this paper. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: We used genotype and gene expression data from ALSPAC, TwinsUK, CoLaus, GEUVADIS, MRCA, MRCE, GENCORD, GTEx v8 and CAP studies. For replication, we used data from the MAGE cohort. The RNA sequencing and genotype data from the GEUVADIS and MAGE studies was publicly available as part of the 1000 Genomes project. For the other studies, we applied for access to individual-level data via relevant data access committees (DACs), explaining the aim of our project and the intent to publicly share meta-analysis summary statistics. Informed consent was obtained when research participants joined the ten studies listed above. The use of the CAP data for this project was approved by the National Heart, Lung and Blood Institute DAC. The use of the GTEx data for this project was approved by the National Human Genome Research Institute DAC. The use of the GENCORD data for this project was approved by the GENCORD DAC. The use of the MRCA and MRCE data for this project was approved by the Gabriel Consortium DAC. The use of TwinsUK data for this project was approved by the TwinsUK Resource Executive Committee. The use of the ALSPAC data for this project was approved by the ALSPAC Executive Committee. For the ALSPAC cohort, ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). The CoLaus study was approved by the Institutional Ethics Committee of the University of Lausanne. Single-cell RNA-seq samples were sourced ethically, and their research use was in accord with the terms of informed consent under an institutional review board/ethics committee-approved protocol (UK Regional Ethics Committee approval granted to work at Wellcome Sanger Institute, protocol reference number 15/NW/0282; project was approved by the Ethics on Research Committee of the Institute of Neurobiology at Universidad Nacional Autonoma de Mexico (UNAM), with the approval number 110.H.). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The whole genome sequencing data for the GEUVADIS and MAGE studies was downloaded from the 1000 Genomes website. The GEUVADIS RNA-seq data was downloaded from the European Nucleotide Archive (ENA) under accession PRJEB3366. The MAGE RNA-seq data was downloaded from the ENA (accession PRJNA851328). The genotype and RNA-seq data from the GENCORD study was downloaded from European Genotype-phenotype Archive (EGA) under accessions EGAD00001000425 and EGAD00001000428. The microarray gene expression data from the MRCA and MRCE studies was downloaded from ArrayExpress (E-MTAB-1425 and E-MTAB-1428) and the genotype data was downloaded from EGA (EGAS00000000137). The gene expression and genotype data from GTEx and CAP studies was downloaded from dbGaP (accessions phs000424.v8.p2 and phs000481.v3.p2). The RNA-seq data from the TwinsUK study was downloaded from EGA (EGAD00001001086) and genotype data was obtained from TwinsUK (https://twinsuk.ac.uk/resources-for-researchers/access-our-data/). The informed consent obtained from ALSPAC participants does not allow the microarray and genotype data to be made freely available through any third party maintained public repository. However, data used for this study can be made available on request to the ALSPAC Executive. The ALSPAC data management plan describes in detail the policy regarding data sharing, which is through a system of managed open access. Full instructions for applying for data access can be found here: http://www.bristol.ac.uk/alspac/researchers/access/. The ALSPAC study website contains details of all the data that are available (http://www.bristol.ac.uk/alspac/researchers/our-data/). The RNA-seq and genotype data from the CoLaus cohort can be accessed by directly contacting the cohort (https://www.colaus-psycolaus.ch/professionals/how-to-collaborate/). The MetaLCL full trans-eQTL meta-analysis summary statistics are available from the eQTL Catalogue FTP server (https://www.ebi.ac.uk/eqtl/Data_access/) and additional documentation is available on the project website (https://github.com/AlasooLab/MetaLCL).