Genome-wide association and whole exome sequencing studies reveal a novel candidate locus for restless legs syndrome

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. 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. 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. Linkage analysis with subsequent association study of exome variants identified six new genes associated with RLS mapped on 7q21 and q22.