Gene Variant Found for Periodic Limb Movements in Sleep
Gene Variant Found for Periodic Limb Movements in Sleep
July 20, 2007 — Researchers have identified the first gene variant associated with susceptibility to periodic limb movements in sleep, involuntary movements that are present in most patients with restless legs syndrome (RLS). An inverse correlation of the variant with iron stores is consistent with the suspected role of iron depletion in the pathogenesis of RLS, they write.
The report was published online July 18 and will appear in the August 16 issue of the New England Journal of Medicine.
The work was a collaboration between an international group of researchers at deCODE Genetics and the Landspitalinn University Hospital and Clinical Research Center, in Rekjavik, Iceland; Emory University, in Atlanta, Georgia; the Hospital Clinic de Barcelona, in Spain; and King's College, in London, United Kingdom.
"We now have concrete evidence that RLS is an authentic disorder with recognizable features and underlying biological basis," said David Rye, MD, PhD, professor of neurology at Emory University School of Medicine, director of the Emory Healthcare Program in Sleep, and 1 of the study's lead authors, in a statement from Emory. "This is the most definitive link between genetics and RLS that has been reported to date. We have known for quite some time that the majority of RLS patients have a close family member with the disorder, and now we have found a gene that is clearly linked to RLS," he said.
The population-attributable risk for RLS with periodic movements in sleep with this variant is approximately 50%, the researchers note. First author on the paper is Hreinn Stefansson, PhD, chief executive officer of deCODE Genetics.
A second study, led by Juliane Winkelmann from the Institute of Human Genetics in Munich, Germany and also published online July 18, in Nature Genetics, confirms the involvement of this variant and adds 2 other possible variants to the mix, all of which were associated with a more than 50% increased risk for RLS.
Major Cause of Sleep Disruption
Restless legs syndrome is a common neurologic disorder with both sensory and motor symptoms. A distressing urge to move the legs during rest or inactivity at night or in the evening is often accompanied by involuntary, highly stereotypical limb movements during sleep called period limb movements in sleep, the authors write.
A substantial genetic contribution to RLS has been well documented, they note. However, "identification of the genetic underpinnings has been challenging because of age-dependent expressivity; the influences of anemia, uremia, diabetes, and peripheral neuropathy; and possibly the modulation of phenotype by body iron stores."
Periodic limb movements in sleep are detectable in most patients with RLS, the authors note. To minimize phenotypic heterogeneity in this study, Dr. Stefansson and colleagues limited their investigation to RLS patients who had objectively documented periodic limb movements in sleep. They carried out a genomewide association study and 2 replication studies, looking for sequence variants contributing to RLS. They also measured serum ferritin, because iron depletion has previously been linked with the pathogenesis of RLS.
In the initial sample of 306 RLS patients with periodic limb movements in sleep from Iceland, the researchers found a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2, with an odds ratio of 1.8 ( P = 2x10 ).
They then tried to replicate that finding in a second Icelandic sample of similar patients and found a similar significant association, with an odds ratio again of 1.8 ( P = 4x10 ). The association was then replicated in a US sample of 188 patients, with an odds ratio this time of 1.5 ( P = 4x10 ).
With this variant, namely the A allele of markerrs3923809, they estimated the population-attributable risk for RLS with periodic limb movements in sleep to be approximately 50%.
Interestingly, serum ferritin levels were decreased by 13% per allele of the at-risk variant, they write (95% CI, 5 – 20%; P = .002)
"The association between a sequence variant and subjects who have periodic limb movements without RLS — and the absence of such an association in subjects with RLS without periodic limb movements — suggest that we have identified a genetic determinant of periodic limb movements in sleep," they write. "Further study is required to determine whether the A allele of marker rs3923809 is associated with periodic limb movements outside the context of RLS," they conclude. "It also remains to be determined whether a sequence variant for RLS without periodic limb movements can be found."
In an interview with Medscape, Dr. Rye said that the fact that this genetic variant is related to periodic limb movements in sleep and to low iron "speaks to the fact that this gene has something intimate to do with this disorder."
This variant is common in the population, found in about 65% of Northern Europeans, Dr. Rye pointed out. However, about 35% of Japanese have the variant, where, perhaps not coincidentally, the prevalence of RLS is about half that of Western populations, he noted. "I think with this, we can explain a lot of what's been described on the epidemiologic side of restless legs concerning frequency in the population, the effects of iron, and that if you have 2 copies of this gene you're twice as likely to kick as someone with 1 copy — and the kicking you do is twice as frequent, so there's a dose-effect on symptoms."
In the "bigger picture," he added, it may also provide insight into more general sleep biology and other sleep disorders, as well as potentially circadian rhythms, given that RLS typically manifests sensory symptoms between 10 PM and 2 AM.
Supportive Findings
Their finding was supported by a second paper that was published simultaneously July 18 by Juliane Winkelmann, MD, from the Institute of Human Genetics in Munich, Germany and colleagues in Nature Genetics. Using German and Canadian cohorts, Dr. Winkelmann and colleagues identified significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene variant also described by Stefansson and colleagues, and a third locus containing genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p, and 15q, respectively, the authors write.
"Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk," the authors write. " MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder."
A "Bona Fide Disorder"
In an editorial accompanying the New England Journal of Medicine paper, John W. Winkelman, MD, PhD, from Brigham and Women's Hospital, in Boston, Massachusetts, points out that some of the earliest descriptions of RLS recognized the strong familial nature, and although recent linkage studies have shown a number of susceptibility loci for RLS, no gene has been identified until now. "For this reason, the report by Stefansson et al in this issue of the Journal showing an association between a sequence variant in chromosome 6p and periodic limb movements in sleep in distinct Icelandic and American cohorts of subjects with RLS and their families, as well as controls, is exciting and important."
He adds, though, that "inspection of the data provided by Stefansson et al, however, shows that this sequence variant does not appear to be a gene for RLS but, rather, for periodic limb movements in sleep."
The highest odds ratios were seen in those with periodic limb movements in sleep without RLS, and the association became less and less apparent as more patients with RLS were added, he notes. The association was not seen at all in those with RLS without periodic limb movements in sleep.
However, there may still be value in knowing the genetic basis for these movements, as it is possible that periodic limb movements in sleep may be used as a heritable biologic marker, or "endophenotype," for RLS, he writes. For example, it may aid in linkage to other relevant susceptibility genes to illuminate polygenic interactions, he notes.
Dr. Winkelman asserts, though, that the demonstration of a strong association between a sequence variant and periodic limb movements in sleep, and to a lesser extent, RLS, is not what validates RLS as a genuine disorder.
"The legitimacy of RLS as a bona fide disorder is provided by the clinically apparent and well-documented sleep disturbance and distress of the roughly 3% of the adult population with frequent and bothersome RLS symptoms," he concludes. "The genetic finding reported by Stefansson et al offers hope to patients with periodic limb movements in sleep and RLS that the syndrome's pathophysiology will be understood and that such knowledge will lead to additional effective and durable treatments."
In response to Dr. Winkelman's comments about the phenotypes of RLS and how they relate to genetic underpinnings, Dr. Rye largely agreed that a potential by-product of these new genetic techniques is that, rather than a group of experts coming to some clinical consensus on what makes up a disorder, these high-throughput techniques are going to provide a genetic definition. "In other words, what is the gene frequency that's discovered with a disorder going to tell us about what the real disorder is?"
The study was supported in part by the Restless Leg Syndrome and Arthur L. Williams Jr. Foundations and the Robert W. Woodruff Health Sciences Fund. Dr. Rye reports receiving consulting fees from or serving on paid advisory boards for GlaxoSmithKline, Boehringer Ingelheim, Ortho-McNeill, and Sepracor and lecture fees from GlaxoSmithKline and Boehringer Ingelheim. Dr. Stefansson is chief executive officer of deCODE Genetics and has equity in the company. The company has a financial interest in the results of the study, including diagnostic products and patents. Disclosures for other coauthors appear in the paper. Dr. Winkelman reports receiving research support and consulting fees from Boehringer Ingelheim, GlaxoSmithKline, and Schwarz Pharma and lecture fees from Boehringer Ingelheim and GlaxoSmithKline; no other potential conflicts were reported.
N Engl J Med. 2007. Published online July 18, 2007.
Nat Genet. 2007. Published online July 18, 2007.
July 20, 2007 — Researchers have identified the first gene variant associated with susceptibility to periodic limb movements in sleep, involuntary movements that are present in most patients with restless legs syndrome (RLS). An inverse correlation of the variant with iron stores is consistent with the suspected role of iron depletion in the pathogenesis of RLS, they write.
The report was published online July 18 and will appear in the August 16 issue of the New England Journal of Medicine.
The work was a collaboration between an international group of researchers at deCODE Genetics and the Landspitalinn University Hospital and Clinical Research Center, in Rekjavik, Iceland; Emory University, in Atlanta, Georgia; the Hospital Clinic de Barcelona, in Spain; and King's College, in London, United Kingdom.
"We now have concrete evidence that RLS is an authentic disorder with recognizable features and underlying biological basis," said David Rye, MD, PhD, professor of neurology at Emory University School of Medicine, director of the Emory Healthcare Program in Sleep, and 1 of the study's lead authors, in a statement from Emory. "This is the most definitive link between genetics and RLS that has been reported to date. We have known for quite some time that the majority of RLS patients have a close family member with the disorder, and now we have found a gene that is clearly linked to RLS," he said.
The population-attributable risk for RLS with periodic movements in sleep with this variant is approximately 50%, the researchers note. First author on the paper is Hreinn Stefansson, PhD, chief executive officer of deCODE Genetics.
A second study, led by Juliane Winkelmann from the Institute of Human Genetics in Munich, Germany and also published online July 18, in Nature Genetics, confirms the involvement of this variant and adds 2 other possible variants to the mix, all of which were associated with a more than 50% increased risk for RLS.
Major Cause of Sleep Disruption
Restless legs syndrome is a common neurologic disorder with both sensory and motor symptoms. A distressing urge to move the legs during rest or inactivity at night or in the evening is often accompanied by involuntary, highly stereotypical limb movements during sleep called period limb movements in sleep, the authors write.
A substantial genetic contribution to RLS has been well documented, they note. However, "identification of the genetic underpinnings has been challenging because of age-dependent expressivity; the influences of anemia, uremia, diabetes, and peripheral neuropathy; and possibly the modulation of phenotype by body iron stores."
Periodic limb movements in sleep are detectable in most patients with RLS, the authors note. To minimize phenotypic heterogeneity in this study, Dr. Stefansson and colleagues limited their investigation to RLS patients who had objectively documented periodic limb movements in sleep. They carried out a genomewide association study and 2 replication studies, looking for sequence variants contributing to RLS. They also measured serum ferritin, because iron depletion has previously been linked with the pathogenesis of RLS.
In the initial sample of 306 RLS patients with periodic limb movements in sleep from Iceland, the researchers found a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2, with an odds ratio of 1.8 ( P = 2x10 ).
They then tried to replicate that finding in a second Icelandic sample of similar patients and found a similar significant association, with an odds ratio again of 1.8 ( P = 4x10 ). The association was then replicated in a US sample of 188 patients, with an odds ratio this time of 1.5 ( P = 4x10 ).
With this variant, namely the A allele of markerrs3923809, they estimated the population-attributable risk for RLS with periodic limb movements in sleep to be approximately 50%.
Interestingly, serum ferritin levels were decreased by 13% per allele of the at-risk variant, they write (95% CI, 5 – 20%; P = .002)
"The association between a sequence variant and subjects who have periodic limb movements without RLS — and the absence of such an association in subjects with RLS without periodic limb movements — suggest that we have identified a genetic determinant of periodic limb movements in sleep," they write. "Further study is required to determine whether the A allele of marker rs3923809 is associated with periodic limb movements outside the context of RLS," they conclude. "It also remains to be determined whether a sequence variant for RLS without periodic limb movements can be found."
In an interview with Medscape, Dr. Rye said that the fact that this genetic variant is related to periodic limb movements in sleep and to low iron "speaks to the fact that this gene has something intimate to do with this disorder."
This variant is common in the population, found in about 65% of Northern Europeans, Dr. Rye pointed out. However, about 35% of Japanese have the variant, where, perhaps not coincidentally, the prevalence of RLS is about half that of Western populations, he noted. "I think with this, we can explain a lot of what's been described on the epidemiologic side of restless legs concerning frequency in the population, the effects of iron, and that if you have 2 copies of this gene you're twice as likely to kick as someone with 1 copy — and the kicking you do is twice as frequent, so there's a dose-effect on symptoms."
In the "bigger picture," he added, it may also provide insight into more general sleep biology and other sleep disorders, as well as potentially circadian rhythms, given that RLS typically manifests sensory symptoms between 10 PM and 2 AM.
Supportive Findings
Their finding was supported by a second paper that was published simultaneously July 18 by Juliane Winkelmann, MD, from the Institute of Human Genetics in Munich, Germany and colleagues in Nature Genetics. Using German and Canadian cohorts, Dr. Winkelmann and colleagues identified significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene variant also described by Stefansson and colleagues, and a third locus containing genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p, and 15q, respectively, the authors write.
"Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk," the authors write. " MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder."
A "Bona Fide Disorder"
In an editorial accompanying the New England Journal of Medicine paper, John W. Winkelman, MD, PhD, from Brigham and Women's Hospital, in Boston, Massachusetts, points out that some of the earliest descriptions of RLS recognized the strong familial nature, and although recent linkage studies have shown a number of susceptibility loci for RLS, no gene has been identified until now. "For this reason, the report by Stefansson et al in this issue of the Journal showing an association between a sequence variant in chromosome 6p and periodic limb movements in sleep in distinct Icelandic and American cohorts of subjects with RLS and their families, as well as controls, is exciting and important."
He adds, though, that "inspection of the data provided by Stefansson et al, however, shows that this sequence variant does not appear to be a gene for RLS but, rather, for periodic limb movements in sleep."
The highest odds ratios were seen in those with periodic limb movements in sleep without RLS, and the association became less and less apparent as more patients with RLS were added, he notes. The association was not seen at all in those with RLS without periodic limb movements in sleep.
However, there may still be value in knowing the genetic basis for these movements, as it is possible that periodic limb movements in sleep may be used as a heritable biologic marker, or "endophenotype," for RLS, he writes. For example, it may aid in linkage to other relevant susceptibility genes to illuminate polygenic interactions, he notes.
Dr. Winkelman asserts, though, that the demonstration of a strong association between a sequence variant and periodic limb movements in sleep, and to a lesser extent, RLS, is not what validates RLS as a genuine disorder.
"The legitimacy of RLS as a bona fide disorder is provided by the clinically apparent and well-documented sleep disturbance and distress of the roughly 3% of the adult population with frequent and bothersome RLS symptoms," he concludes. "The genetic finding reported by Stefansson et al offers hope to patients with periodic limb movements in sleep and RLS that the syndrome's pathophysiology will be understood and that such knowledge will lead to additional effective and durable treatments."
In response to Dr. Winkelman's comments about the phenotypes of RLS and how they relate to genetic underpinnings, Dr. Rye largely agreed that a potential by-product of these new genetic techniques is that, rather than a group of experts coming to some clinical consensus on what makes up a disorder, these high-throughput techniques are going to provide a genetic definition. "In other words, what is the gene frequency that's discovered with a disorder going to tell us about what the real disorder is?"
The study was supported in part by the Restless Leg Syndrome and Arthur L. Williams Jr. Foundations and the Robert W. Woodruff Health Sciences Fund. Dr. Rye reports receiving consulting fees from or serving on paid advisory boards for GlaxoSmithKline, Boehringer Ingelheim, Ortho-McNeill, and Sepracor and lecture fees from GlaxoSmithKline and Boehringer Ingelheim. Dr. Stefansson is chief executive officer of deCODE Genetics and has equity in the company. The company has a financial interest in the results of the study, including diagnostic products and patents. Disclosures for other coauthors appear in the paper. Dr. Winkelman reports receiving research support and consulting fees from Boehringer Ingelheim, GlaxoSmithKline, and Schwarz Pharma and lecture fees from Boehringer Ingelheim and GlaxoSmithKline; no other potential conflicts were reported.
N Engl J Med. 2007. Published online July 18, 2007.
Nat Genet. 2007. Published online July 18, 2007.
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