• DOI:10.1056/NEJMOA072743
• Corpus ID: 44726156

A genetic risk factor for periodic limb movements in sleep.

@article{Stefnsson2007AGR,
  title={A genetic risk factor for periodic limb movements in sleep.},
  author={Hreinn Stef{\'a}nsson and David B. Rye and Andrew A. Hicks and Hjorvar Petursson and Andr{\'e}s Ingason and Thorgeir E. Thorgeirsson and Stefan Th Palsson and Thordur Sigmundsson and Albert P{\'a}ll Sigurdsson and Ingibjorg Eiriksdottir and Emilia Soebech and Donald L. Bliwise and Joseph M Beck and Ami R. Rosen and Salina P. Waddy and Lynn Marie Trotti and {\'A}lex Iranzo and Madhav Thambisetty and Gudmundur A. Hardarson and Kristleifur Kristj{\'a}nsson and L{\'a}rus J. Gudmundsson and Unnur Thorsteinsd{\'o}ttir and Augustine Kong and Jeffrey R. Gulcher and Daniel Fannar Gudbjartsson and K{\'a}ri Stef{\'a}nsson},
  journal={The New England journal of medicine},
  year={2007},
  volume={357 7},
  pages={
          639-47
        }
}

• H. Stefánsson, D. Rye, +23 authors K. Stefánsson
• Published 16 August 2007
• Biology, Medicine
• The New England journal of medicine

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.