Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome

Abstract

Sixty percent of the patients with restless legs syndrome (RLS) report a positive family history. To date five loci have been mapped on chromosome 12q, 14q, 9p, 2q, and 20p (RLS1-5) but no gene has been identified so far. To identify genes related to RLS, we performed a three-stage association study (explorative study, replication study, high-density mapping) in two Caucasian RLS case-control samples of altogether 918 independent cases and controls. In the explorative study (367 cases and controls, respectively), we screened 1536 SNPs in 366 genes in a 21 Mb region encompassing the RLS1 critical region on chromosome 12. Armitage trend test revealed three genomic regions that were significant (P < 0.05). In the replication study (551 cases and controls, respectively) we genotyped the most significant SNPs of Stage 1. After correction for multiple testing, association was observed with SNP rs7977109 (P(nominal) = 0.00175, P(Westfall-Young) = 0.04895, OR = 0.76228, 95% CI = 0.64310-0.90355), which is in the neuronal nitric oxide synthase (NOS1) gene. High-density mapping using altogether 34 tagging and coding SNPs of the NOS1 gene in both case-control samples further confirmed the significant association results to NOS1. Ten more SNPs revealed significance with nominal P-values from 0.0001 to 0.0482 (genotypic test and Armitage test). Altogether, this study provides evidence for an association of variants in the NOS1 gene and RLS, and suggests the involvement of the NO/arginine pathway in the pathogenesis of RLS. Potential usage of NO modulating agents as new treatment options for RLS have become a challenging aspect for future research of this disorder.

Genetic and Immunologic Aspects of Sleep and Sleep Disorders

“…20 Genetic linkage studies in these families have identified several associated chromosomal loci: RLS1 on chromosome 12q, discovered in a French Canadian family 21 ; RLS2 on 14q, in an Italian family 22 ; RLS3 on chromosome 9p, in 15 extended American families; RLS4 on chromosome 2q; and RLS5 on chromosome 20p. 23 In these families, transmission appears to be autosomal dominant with incomplete penetrance. A high concordance has been found in monozygotic twins.…”

Cardiovascular comorbidity in patients with restless legs syndrome: current perspectives

“…This study supports the involvement of the NO/arginine pathway in the pathogenesis of RLS. 82 Intermittent hypoxia and hypoxia response pathways (cell survival pathways) have been suggested as a possible mechanism in the pathogenesis of RLS, 84 and thus increased risk of CVDs. An important survival pathway is the hypoxiainducible factor-1 (HIF-1).…”

Genome-Wide Association Studies of Sleep Disorders

“…The same group applied a similar approach for identifying RLS-associated SNPs in a 21-Mb region of chromosome 12q, 52 another region previously implicated in linkage studies. 33 , 53 , 54 They further reduced the number of tested SNPs and the size of the explored genome to 12.5 Mb by excluding SNPs located in regions between genes.…”