Genome-Wide Association and Whole Exome Sequencing Studies reveal a Novel Candidate Locus for Restless Legs Syndrome

INTRODUCTION:The restless legs syndrome (RLS) is a common heritable neurologic disorder which is characterized by an irresistible desire to move and unpleasant sensations in the legs. METHODS:We aim to identify new variants associated with RLS by performing genome-wide linkage and subsequent association analysis of forty member's family with history of RLS. RESULTS:We found evidence of linkage for three loci 7q21.11 (HLOD = 3.02), 7q21.13-7q21.3 (HLOD = 3.02) and 7q22.3 (HLOD = 3.09). Fine-mapping of those regions in association study using exome sequencing identified SEMA3A (p-value = 8.5·10-4), PPP1R9A (p-value = 7.2·10-4), PUS7 (p-value = 8.7·10-4), CDHR3 (p-value = 7.2·10-4), HBP1 (p-value = 1.5·10-4) and COG5 (p-value = 1.5·10-4) genes with p-values below significance threshold. CONCLUSION:Linkage analysis with subsequent association study of exome variants identified six new genes associated with RLS mapped on 7q21 and q22.