Genetic variants at the locus are associated with fatigue in Scandinavian patients with primary Sjögren's syndrome.

Objectives: Fatigue is common and severe in primary Sjögren's syndrome (pSS). The aim of this study was to identify genetic determinants of fatigue in pSS through a genome-wide association study.

Methods: Patients with pSS from Norway, Sweden, UK and USA with fatigue and genotype data available were included. After genotype imputation and quality control, 682 patients and 4 966 157 genetic markers were available. Association analysis in each cohort using linear regression with fatigue as a continuous variable and meta-analyses between the cohorts were performed.

Results: Meta-analysis of the Norwegian and Swedish cohorts identified five polymorphisms within the same linkage disequilibrium block at the receptor transporter protein 4 ( locus associated with fatigue with genome-wide significance (GWS) (p<5×10). Patients homozygous for the major allele scored 25 mm higher on the fatigue Visual Analogue Scale than patients homozygous for the minor allele. There were no variants associated with fatigue with GWS in meta-analyses of the US/UK cohorts, or all four cohorts. expression in pSS B cells was upregulated and positively correlated with the type I interferon score. Expression quantitative trait loci effects in whole blood for fatigue-associated variants at and levels of and expression were identified.

Conclusion: Genetic variations at are associated with fatigue in Scandinavian pSS patients. encodes a Golgi chaperone that influences opioid pain receptor function and is involved in complement activation. These results add evidence for genetic influence over fatigue in pSS.