The Genetic Etiology of Periodic Leg Movement in Sleep.
Sleep. 2022 Jun 7:zsac121. doi: 10.1093/sleep/zsac121. Epub ahead of print. PMID: 35670608
| Authors/Editors: | Edelson JL, Schneider LD, Amar D, Brink-Kjaer A, Cederberg KL, Kutalik Z, Hagen EW, Peppard PE, Tempaku PF, Tufik S, Evans DS, Stone K, Tranah G, Cade B, Redline S, Haba-Rubio J, Heinzer R, Marques-Vidal P, Vollenweider P, Winkelmann J, , Zou J, Mignot E. |
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| Publication Date: | 2022 |
Abstract
Study Objectives: Periodic Limb Movement in Sleep is a common sleep phenotype
characterized by repetitive leg movements that occur during or before sleep. We conducted
a Genome-Wide Association Study (GWAS) of periodic limb movements in sleep (PLMS)
using a joint analysis (i.e., discovery, replication, and joint meta-analysis) of 4 cohorts
(MrOS, the Wisconsin Sleep Cohort Study, HypnoLaus, and MESA), comprised of 6,843
total subjects.
Methods: The MrOS study and Wisconsin Sleep Cohort Study (N=1,745 cases) were used
for discovery. Replication in the HypnoLaus and MESA cohorts (1,002 cases) preceded joint
meta-analysis. We also performed LD score regression, estimated heritability, and computed
genetic correlations between potentially associated traits such as restless leg syndrome
(RLS) and insomnia. The causality and direction of the relationships between PLMS and
RLS was evaluated using mendelian randomization.
Results: We found 2 independent loci were significantly associated with PLMS:
rs113851554 (p = 3.51 x 10-12, beta=0.486), a SNP located in a putative regulatory element
of intron eight of MEIS1 (2p14); and rs9369062 (p = 3.06 x10-22, beta=0.2093), a SNP
located in the intron region of BTBD9 (6p12); both of which were also lead signals in RLS
GWAS. PLMS is genetically correlated with insomnia, risk of stroke, and RLS, but not with
iron deficiency. Pleiotropy adjusted Mendelian randomization analysis identified a causal
effect of RLS on PLMS.
Conclusions: Because PLMS is more common than RLS, PLMS may have multiple causes
and additional studies are needed to further validate these findings.
Statement of Significance: This is the first study to explore the genetics of periodic limb
movement in sleep (PLMS) and determine if there is overlapping shared genetic architecture
between PLMS and Restless leg syndrome (RLS) and other sleep phenotypes. We found
two genes, BTBD9 and MEIS1, reached genome-wide significance in their association with
PLMS. In addition, we also found a high correlation between PLMS and a genetic
predisposition to stroke as well as RLS, and a relatively weak association with insomnia, and
finally, using a Mendelian Randomization approach, we found that RLS is causally
associated with PLMS. Additional studies of this phenotype are warranted considering its
high prevalence and the possibility that it could predispose to a variety of clinically significant
cardiovascular outcomes.
