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Previous Volume 357:639-647 August 16, 2007 Number 7 Next

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ABSTRACT

Background 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.

Methods 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.

Results 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).

Conclusions 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.

Source Information

From deCODE Genetics (H.S., A.H., H.P., A. Ingason, T.E.T., S.P., E.S., G.A.H., K.K., L.J.G., U.T., A.K., J.R.G., D.G., K.S.), Landspítalinn University Hospital (T.S., A.P.S.), and Clinical Research Center (I.E.) — all in Reykjavik, Iceland; the Department of Neurology and Program in Sleep, Emory University, Atlanta (D.B.R., D.B., J.M.B., A.R., S.W., L.M.T.); Neurology Service, Hospital Clinic de Barcelona, Barcelona (A. Iranzo); and Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, King's College, London (M.T.).

Drs. H. Stefansson, Rye, and Hicks contributed equally to this article.

This article (10.1056/NEJMoa072743) was published at www.nejm.org on July 18, 2007.

Address reprint requests to Dr. K. Stefansson at 1 deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland, or at kstefans{at}decode.is.

Full Text of this Article

Related Letters:

A Genetic Risk Factor for Periodic Limb Movements in Sleep
Vilariño-Güell C., Farrer M. J., Lin S.-C., Woloshin S., Schwartz L. M.
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N Engl J Med 2008; 358:425-428, Jan 24, 2008. Correspondence

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