Studies demonstrate a strong relationship between genetic predisposition and early-onset RLS, of which more than 60% reveal a positive familial history. Moreover, inheritance was found to be related to late-onset RLS and secondary RLS (Winkelmann et al., 2000; Xiong et al., 2010; Yang et al., 2011). A study among 249 Canadian RLS patients found a family history existed in 77.1% of them while the rest 22.9% were sporadic (Yang et al., 2011). Variants in MEIS1, BTBD9 and MAP2K5/SKOR1 resulted in a much higher risk of RLS among a US population (Yang et al., 2011). So far, the GWASs have reported the following susceptible SNPs in association with RLS: MEIS1 (chromosome 2p14), BTBD9 (chromosome 6p21.2), PTPRD (chromosome 9p24.1-p23), MAP2K5/SCOR1 (chromosome 15q23) and chromosome 16q12.1 (Berger et al., 2002; Hogl et al., 2005; Stefansson et al., 2007; Schormair et al., 2008). Main function of these genes was related to embryonic neuronal development and limb development (Dauvilliers and Winkelmann, 2013; Garcia-Borreguero and Williams, 2014). In RLS autopsy cases, MEIS1 gene was found to be associated with an increase in H-ferritin, L-ferritin and divalent metal transporter-1 RNA expression in the thalamus (Catoire et al., 2011), suggesting MEIS1 gene mutants predisposed to lower iron condition. Another study used RNA interference techniques in a lymphoblastoid cell line in which the MEIS mRNA expression was blocked (Silver et al., 2010). Forty-eight hours later, an increase in transferring-2 receptor, ferroportin mRNA and BTBD9, and a decrease in hepcidin mRNA expression were observed (Silver et al., 2010), indicating that MEIS1 controlled cellular iron transfer to mitochondria, cellular export of iron and potentially affected BTBD9 expression and its downstream iron modulation. The effect of MEIS1 on iron homeostasis was also shown in Caenorhabditis elegans (Catoire et al., 2011). A study using dBTBD9 mutant flies showed significantly decreased brain dopamine and abnormal sleep phenotype which was completely retrieved by administering with pramipexole, a dopamine D2 receptor agonist (Freeman et al., 2012). Furthermore, RLS symptoms can be reconstructed by knocking-down dBTBD9 expression. While over expression of BTBD9 in HEK cells showed that the gene controlled iron homeostasis through the regulation of IRP2 (Freeman et al., 2012). The authors suggested that the BTBD9 protein belonged to a protein family which contained substrate adaptors for the Cul3 class (Freeman et al., 2012). Cul3 class of E3 ubiquitin ligases was shown to regulate sleep in flies (Stavropoulos and Young, 2011). A susceptible view point was that BTBD9 played a role in dopamine biosynthesis by unclear mechanisms (Shaw and Duntley, 2012). These SNPs had strong association with PLM in RLS patients (Moore et al., 2014). The exact pathophysiological pathways of these genes still remain unclear. An SNP study in the Spanish Caucasian population suggested a modest but significant association between vitamin D receptor rs731236 SNP and the risk for RLS. RLS patients carrying the allelic variant rs731236G had an earlier onset age while those carrying the allelic variant rs731236GG had more severe symptoms (Jimenez-Jimenez et al., 2015). A weak association between heme oxygenase genetic variants HMOX1 rs2071746 polymorphism and the risk of developing RLS was found in the Spanish population (Garcia-Martin et al., 2015). Linkage analyses in families identified several genetic loci for RLS: RLS1 (chromosome 12q12–q21), RLS2 (14q13–q21), RLS3 (9p24–p22), RLS4 (2q33), RLS5 (20p13), RLS6 (19p13), and RLS7 (16p12.1) (Desautels et al., 2001, 2005; Bonati et al., 2003; Kemlink et al., 2007). The authors suggested the inheritance mode of RLS could be a recessive mode or a dominant mode with variable of inheritance. The main SNP findings are summarized as below (Table 3).