The Genetic Etiology of Periodic Leg Movement in Sleep. Sleep Edelson, J. L., Schneider, L. D., Amar, D., Brink-Kjaer, A., Cederberg, K. L., Kutalik, Z., Hagen, E. W., Peppard, P. E., Tempaku, P. F., Tufik, S., Evans, D. S., Stone, K., Tranah, G., Cade, B., Redline, S., Haba-Rubio, J., Heinzer, R., Marques-Vidal, P., Vollenweider, P., Winkelmann, J., Zou, J., Mignot, E. 2022


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.

View details for DOI 10.1093/sleep/zsac121

View details for PubMedID 35670608