A genetic risk factor for periodic limb movements in sleep.
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.
Stefansson
Hreinn
H
deCODE Genetics, Reykjavik, Iceland. kstefans@decode.is
Rye
David B
DB
Hicks
Andrew
A
Petursson
Hjorvar
H
Ingason
Andres
A
Thorgeirsson
Thorgeir E
TE
Palsson
Stefan
S
Sigmundsson
Thordur
T
Sigurdsson
Albert P
AP
Eiriksdottir
Ingibjorg
I
Soebech
Emilia
E
Bliwise
Donald
D
Beck
Joseph M
JM
Rosen
Ami
A
Waddy
Salina
S
Trotti
Lynn M
LM
Iranzo
Alex
A
Thambisetty
Madhav
M
Hardarson
Gudmundur A
GA
Kristjansson
Kristleifur
K
Gudmundsson
Larus J
LJ
Thorsteinsdottir
Unnur
U
Kong
Augustine
A
Gulcher
Jeffrey R
JR
Gudbjartsson
Daniel
D
Stefansson
Kari
K
D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6; D005260:Female; D005293:Ferritins / Q000097:blood; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D000090463:Iron Deficiencies; D015810:Linkage Disequilibrium; D008297:Male; D009419:Nerve Tissue Proteins; D020189:Nocturnal Myoclonus Syndrome / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012148:Restless Legs Syndrome / Q000097:blood / Q000235:genetics*; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*
C522207:BTBD9 protein, human; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D005293:Ferritins