Department of Biomedical Data Sciences, Stanford University School of Medicine, Palo Alto, CA 94603, USA.
Stanford/VA Alzheimer's Research Center, Palo Alto, CA 94603, USA.
Sleep. 2023 Apr 12;46(4). doi: 10.1093/sleep/zsac121.
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 four cohorts (MrOS, the Wisconsin Sleep Cohort Study, HypnoLaus, and MESA), comprised of 6843 total subjects.
The MrOS study and Wisconsin Sleep Cohort Study (N = 1745 cases) were used for discovery. Replication in the HypnoLaus and MESA cohorts (1002 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.
We found 2 independent loci were significantly associated with PLMS: rs113851554 (p = 3.51 × 10-12, β = 0.486), an SNP located in a putative regulatory element of intron eight of MEIS1 (2p14); and rs9369062 (p = 3.06 × 10-22, β = 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.
Because PLMS is more common than RLS, PLMS may have multiple causes and additional studies are needed to further validate these findings.
周期性肢体运动在睡眠中是一种常见的睡眠表型，其特征是在睡眠期间或之前发生的重复性腿部运动。我们使用四个队列（MrOS、威斯康星州睡眠队列研究、HypnoLaus 和 MESA）的联合分析（即发现、复制和联合荟萃分析）对睡眠中的周期性肢体运动（PLMS）进行了全基因组关联研究（GWAS），共包括 6843 名受试者。
MrOS 研究和威斯康星州睡眠队列研究（N=1745 例）用于发现。HypnoLaus 和 MESA 队列的复制（1002 例）先于联合荟萃分析。我们还进行了 LD 得分回归、遗传力估计，并计算了潜在相关特征（如不宁腿综合征（RLS）和失眠）之间的遗传相关性。使用孟德尔随机化评估了 PLMS 和 RLS 之间关系的因果关系和方向。
我们发现 2 个独立的基因座与 PLMS 显著相关：rs113851554（p=3.51×10-12，β=0.486），位于 MEIS1 内含子 8 中一个假定调节元件的 SNP；rs9369062（p=3.06×10-22，β=0.2093），位于 BTBD9（6p12）内含子区域的 SNP；这两个 SNP 也是 RLS GWAS 的主要信号。PLMS 与失眠、中风风险和 RLS 具有遗传相关性，但与缺铁无关。多效性调整的孟德尔随机化分析确定了 RLS 对 PLMS 的因果影响。
由于 PLMS 比 RLS 更常见，PLMS 可能有多种原因，需要进一步的研究来进一步验证这些发现。
