2.50
Hdl Handle:
http://hdl.handle.net/2336/14500
Title:
A genetic risk factor for periodic limb movements in sleep
Authors:
Stefansson, Hreinn; Rye, David B; Hicks, Andrew; Petursson, Hjorvar; Ingason, Andres; Thorgeirsson, Thorgeir E; Palsson, Stefan; Sigmundsson, Thordur; Sigurdsson, Albert P; Eiriksdottir, Ingibjorg; Soebech, Emilia; Bliwise, Donald; Beck, Joseph M; Rosen, Ami; Waddy, Salina; Trotti, Lynn M; Iranzo, Alex; Thambisetty, Madhav; Hardarson, Gudmundur A; Kristjansson, Kristleifur; Gudmundsson, Larus J; Thorsteinsdottir, Unnur; Kong, Augustine; Gulcher, Jeffrey R; Gudbjartsson, Daniel; Stefansson, Kari
Citation:
N. Engl. J. Med. 2007, 357(7):639-47
Issue Date:
16-Aug-2007
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.
Description:
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field
Additional Links:
http://content.nejm.org/cgi/content/abstract/357/7/639

Full metadata record

DC FieldValue Language
dc.contributor.authorStefansson, Hreinn-
dc.contributor.authorRye, David B-
dc.contributor.authorHicks, Andrew-
dc.contributor.authorPetursson, Hjorvar-
dc.contributor.authorIngason, Andres-
dc.contributor.authorThorgeirsson, Thorgeir E-
dc.contributor.authorPalsson, Stefan-
dc.contributor.authorSigmundsson, Thordur-
dc.contributor.authorSigurdsson, Albert P-
dc.contributor.authorEiriksdottir, Ingibjorg-
dc.contributor.authorSoebech, Emilia-
dc.contributor.authorBliwise, Donald-
dc.contributor.authorBeck, Joseph M-
dc.contributor.authorRosen, Ami-
dc.contributor.authorWaddy, Salina-
dc.contributor.authorTrotti, Lynn M-
dc.contributor.authorIranzo, Alex-
dc.contributor.authorThambisetty, Madhav-
dc.contributor.authorHardarson, Gudmundur A-
dc.contributor.authorKristjansson, Kristleifur-
dc.contributor.authorGudmundsson, Larus J-
dc.contributor.authorThorsteinsdottir, Unnur-
dc.contributor.authorKong, Augustine-
dc.contributor.authorGulcher, Jeffrey R-
dc.contributor.authorGudbjartsson, Daniel-
dc.contributor.authorStefansson, Kari-
dc.date.accessioned2007-11-07T15:55:04Z-
dc.date.available2007-11-07T15:55:04Z-
dc.date.issued2007-08-16-
dc.date.submitted2007-11-07-
dc.identifier.citationN. Engl. J. Med. 2007, 357(7):639-47en
dc.identifier.issn1533-4406-
dc.identifier.pmid17634447-
dc.identifier.doi10.1056/NEJMoa072743-
dc.identifier.urihttp://hdl.handle.net/2336/14500-
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractBACKGROUND: 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.en
dc.language.isoenen
dc.publisherMassachusetts Medical Societyen
dc.relation.urlhttp://content.nejm.org/cgi/content/abstract/357/7/639en
dc.subject.meshChromosomes, Human, Pair 6en
dc.subject.meshFerritinsen
dc.subject.meshGenetic Markersen
dc.subject.meshGenetic Predisposition to Diseaseen
dc.subject.meshGenome, Humanen
dc.subject.meshGenotypeen
dc.subject.meshIronen
dc.subject.meshLinkage Disequilibriumen
dc.subject.meshNocturnal Myoclonus Syndromeen
dc.subject.meshPolymorphism, Single Nucleotideen
dc.subject.meshRestless Legs Syndromeen
dc.subject.meshTranscription Factorsen
dc.titleA genetic risk factor for periodic limb movements in sleepen
dc.typeArticleen
dc.identifier.journalNew England journal of medicineen
dc.format.digYES-

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