Trans-eQTL mapping prioritises USP18 as a negative regulator of interferon response at a lupus risk locus
Freimann K., Brümmer A., Warmerdam R., Rupall TS., Hernández-Ledesma AL., Chiou J., Holzinger ER., Maranville JC., Nakic N., Ongen H., Stefanucci L., Turchin MC., Barturen G., Alarcón-Riquelme ME., Viñuela A., Dupuis T., Brown A., Zhernakova D., Xie M., Wood AR., Westra HJ., Wen J., Weiss S., Wang QS., Völker U., Visscher PM., Verlouw J., Veldink J., Tönjes A., Tong L., Tokolyi A., Thiery J., Teumer A., Tay D., Sung YJ., Stumvoll M., Souto JC., Soria JM., Slagboom E., Singleton A., Scholz M., Sanford J., Rovio SP., Rodríguez RD., Rivas-Torrubia M., Raitoharju E., Raitakari OT., Raghavan V., Raffield L., Prokisch H., Pool R., Pierce B., Peters A., Persyn E., Penninx BWJH., Paul DS., Pasaniuc B., Pahkala K., Ophoff R., Okada Y., Nauck M., Namkoong H., Nagpal S., Naeem H., Mykkänen J., Montgomery GW., Mokrab Y., Mishra PP., Milani L., van Meurs J., McRae AF., Martinez-Perez A., Martin J., Mägi R., Lyytikäinen LP., Loh M., Loeffler M., Li Y., Lehtimäki T., Lapinska S., Kumar V., Kukushkina V., Krohn K., Kovacs P., Knight JC., Kirsten H., Kibriya M., Kähönen M., Johnson M., Jasmine F., Jansen R., Inouye M., Ikram MA., Jan Hottenga J., Hasegawa T., Mishra BH., van Greevenbroek M., Gorijala P., Gieger C., Gibson G.
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.