Article

Stefansson H, Rye D, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep

Emory University, Atlanta, Georgia, United States
New England Journal of Medicine (Impact Factor: 54.42). 09/2007; 357(7):639-47. DOI: 10.1056/NEJMoa072743
Source: PubMed

ABSTRACT The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric.
To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS.
In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002).
We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.

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    • "Enfin, l'hypothèse d'une liaison génétique entre ces deux pathologies a été étudiée. Ainsi, Schimmelmann et al. [33] ont trouvé chez 386 enfants une association significative entre le risque de développer un TDA/H et un polymorphisme nucléotidique (SNP) du gène BTBD9, gène déjà connu pour son implication en tant que gène de susceptibilité du SJSR et de carence martiale [34] [35]. Dans la même perspective, Gao et al. ont mis en évidence un risque accru de SJSR chez les mères d'enfants présentant un TDA/H [36]. "
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    • "GWAS studies and forward genetics studies in animals can be complementary and informative . For example, Winkelmann et al. (2007) and Stefansson et al. (2007) each reported GWAS studies of individuals with restless legs syndrome and periodic limb movements that identified associated genetic markers near BTBD9 gene in humans. Restless legs syndrome and periodic limb movements are associated with low iron in the substantia nigra and related DA dysfunction. "
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    • "Three patients with a family history of idiopathic RLS developed olanzapine induced-RLS, indicating that family history may be a risk factor for the condition; however, the underlying mechanisms are not known. Genome-wide association studies have identified a polymorphism in an intronic region of the BTBD9 gene on chromosome 6 that confers substantial risk for RLS [16] [17]. Furthermore, one study found that loss of BTBD9 significantly disrupted sleep with concomitant increases in waking and motor activity in a Drosophila model [18]. "
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