STUDY OBJECTIVES: Recent genome-wide association studies (GWAS) for Caucasians 
identified several allelic variants associated with increased risk of developing 
restless legs syndrome (RLS), also known as Willis-Ekbom disease. Although the 
pathogenic mechanisms of RLS are not entirely understood, it is becoming 
increasingly evident that many diseases such as RLS can be attributed to an 
epistasis. The study objectives were to evaluate whether the associations of RLS 
with all loci determined in previous GWAS for Caucasians can be replicated 
significantly for the Korean population and to elucidate whether an epistasis 
plays a role in the pathogenesis of RLS.
DESIGN SETTING AND PARTICIPANTS: DNA from 320 patients with RLS and 320 age- and 
sex-matched controls were genotyped for variants in the RLS loci.
MEASUREMENTS AND RESULTS: A significant association was found for rs3923809 and 
rs9296249 in BTBD9 (P < 0.0001 and P = 0.001, respectively); the odds ratio (OR) 
for rs3923809 was 1.61 (P < 0.0001) to 1.88 (P < 0.0001) and the OR for 
rs9296249 was 1.44 (P = 0.001) to 1.73 (P = 0.002), according to the model of 
inheritance. The OR for the interaction between rs3923809 in BTBD9 and rs4626664 
in PTPRD was 2.05 (P < 0.0001) in the additive model, 1.80 (P = 0.002) in the 
dominant model and 2.47 (P = 0.004) in the recessive model. There was no 
significant association between genotypes of all tested single nucleotide 
polymorphisms and the mean value of serum iron parameters.
CONCLUSIONS: Our results suggest that the role of BTBD9 in the pathogenesis of 
restless legs syndrome is more universal across populations than previously 
reported and more efforts should be focused on the role of epistasis in the 
genetic architecture of restless legs syndrome.