Two independent groups of scientists have discovered genes linked to Restless Leg Syndrome (RLS), a disorder that affects millions of people worldwide and causes disturbed sleep. One group also found a link between iron deficiency and a gene associated with RLS.

One study is led by scientists based at Emory University in Atlanta, Georgia, USA, and also from the company deCODE Genetics in Reykjavik, Iceland, and is published in the New England Journal of Medicine (NEJM).

The other study is published in the journal Nature Genetics and was performed by scientists based at the Institute of Human Genetics in Munich, Germany, and other German, Austrian and Canadian universities.

People who have RLS get an irresistible urge to move their legs, especially when lying in bed at night. It is a major disrupter of sleep and affects about 10 per cent of Americans, including one per cent of children. One of the benefits of these discoveries is that it dispels the doubt about whether RLS is a genuine syndrome.

"We now have concrete evidence that RLS is an authentic disorder with recognizable features and underlying biological basis," said Dr David Rye, one of the lead authors of the NEJM study, professor of neurology at Emory University School of Medicine, and director of the Emory Healthcare Program in Sleep.

Rye said that although RLS is very common, because it is not covered in medical training, many health professionals remain sceptical about its authenticity and prevalence.

"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 which is clearly linked to RLS," said Rye.

The NEJM study team was jointly led by Rye and Dr Hreinn Stefansson of deCODE Genetics and took four years to conduct a genome-wide association (GWA) study and two replication studies, using a new chip technology and other GWA techniques. They focussed on patients who had objectively documented periodic limb movements while sleeping and they also measured blood iron (ferritin) levels because low blood ferritin has been linked to RLS.

A total of nearly 1,000 people from Iceland and 188 Americans were involved in the study.

The scientists examined a total of 300,000 bits of DNA (or more accurately single nucleotide polymorphisms, called SNPs or "snips") to find differences between people with and without RLS.

They discovered a significant link between a common variant of a gene called BTBD9 located on chromosome 6p21.2 and RLS and periodic limb movements in sleep. This was found in one Icelandic sample and replicated in two further samples: another in Iceland and one in the US.

According to Rye the variant is very common and at least one copy is carried by 65 per cent of the population. Having both copies more than doubles a person's risk of getting RLS.

Rye and colleagues estimated the population-attributable risk for RLS to be at least 50 per cent (it was 80 per cent in the first sample and 50 in the second). This means if the gene variant were not present, over 50 per cent of RLS cases would not exist.

Having both copies does not mean for certain that a person will experience RLS.

"There remain yet-to-be-identified medical, environmental or genetic factors that appear necessary to translate genetic susceptibility into RLS symptoms," said Rye.

Presence of the gene variant was also inversely linked to ferritin levels in the Icelandic sample, leading to the conclusion that iron depletion is involved in the development of RLS and could be one of the triggers.

Dr John Winkelman of the division of sleep medicine at Boston's Brigham and Women's Hospital and Harvard Medical School wrote in an accompanying editorial in the same NEJM edition that this study offers RLS patients the hope that the syndrome will be better understood and more effective and durable treatments will be developed.

He also said that unravelling the genetic linkages to RLS will help to understand the complex nature of the syndrome, and could reveal it be a combination of conditions each governed by a different genetic link or interplay with environmental factors such as the iron depletion. There may also be other RLS genes out there, he implied.

The study in Nature Genetics also links the BTBD9 gene to RLS and two other variants, one in the MEIS1 gene and another in a "snip" that is common to the genes MAP2K5 and LBXCOR1.

Led by Dr Juliane Winkelmann, of the Institute of Human Genetics in Munich, Germany (unrelated to the editorial writer in the NEJM), the team scanned the genes of over 4,300 German and Canadian subjects, of which at least 1,500 had RLS.

They concluded that each genetic variant was linked to more than 50 per cent increase in the risk of getting RLS, with combinations conferring more than half of it. Other studies have linked the MEIS1 gene to limb development, suggesting that "RLS has components of a developmental disorder", they said.

"A Genetic Risk Factor for Periodic Limb Movements in Sleep."
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.
N Engl J Med Published online July 18, 2007

Click here for full Article.

"Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions."
Juliane Winkelmann, Barbara Schormair, Peter Lichtner, Stephan Ripke, Lan Xiong, Shapour Jalilzadeh, Stephany Fulda, Benno Pütz, Gertrud Eckstein, Stephanie Hauk, Claudia Trenkwalder, Alexander Zimprich, Karin Stiasny-Kolster, Wolfgang Oertel, Cornelius G Bachmann, Walter Paulus, Ines Peglau, Ilonka Eisensehr, Jacques Montplaisir, Gustavo Turecki, Guy Rouleau, Christian Gieger, Thomas Illig, H-Erich Wichmann, Florian Holsboer, Bertram Müller-Myhsok and Thomas Meitinger.
Nature Genetics Published online: 18 July 2007

Click here for Abstract.