The impact of Mendelian sleep and circadian genetic variants in a population setting.
The impact of Mendelian sleep and circadian genetic variants in a population setting.
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DOI：
10.1371/journal.pgen.1010356
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发表时间：
2022-09
期刊：
影响因子：
4.5
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中科院分区：
文献类型：
--
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据报道，10个基因的罕见变异导致孟德尔睡眠状况，其特征是极端的睡眠时间或时间。这些包括家族性自然短睡眠（ADRB 1，DEC 2/BHLHE 41，GRM 1和NPSR 1），提前睡眠阶段（PER 2，PER 3，CSNK 2，CSNK 1D和TIMELESS）和延迟睡眠阶段（TIME 1）。这些基因的变异与极端睡眠条件的关联通常是基于临床确定的家族，而它们在人群中的影响尚不清楚。我们的目的是确定这些变异对大规模人群中睡眠特征的影响。我们对先前报道的孟德尔睡眠和昼夜节律条件的因果变异进行了遗传关联分析。分析使用了191，929名个体的睡眠数据和全外显子组或基因组序列数据，这些数据来自4项基于人群的研究：UK Biobank，FINRISK，Health-2000-2001和多种族动脉粥样硬化研究（梅萨）。我们从自我报告、医院和初级保健数据中确定了睡眠障碍。我们根据自我报告和加速度计数据估计了睡眠持续时间和时间测量。我们确定了10个载体的12个先前报告的致病性变异的10个基因中的8个。他们的频率范围从1个人在CSNK 1D变异到1，574个人在英国生物库中报告的PER 3基因变异。未发现NPSR 1或PER 2中报告的变体的携带者。我们发现分析的变体与极端睡眠或昼夜节律表型之间没有关联。使用睡眠时间作为睡眠阶段的代理指标，只有PER 3和PER 11变体分别与较早和较晚的睡眠时间相关;然而，影响程度小于先前报道的影响程度（睡眠中点分别提前约7分钟和约5分钟）。我们还对10个基因进行了蛋白质截短（PTV）或罕见错义变体的负荷试验。只有PER 2和PER 3中的PTV与相关特征相关（例如，64名PER 2中PTV的个体“绝对是一个早起的人”的比值比为4.4，P = 4x 10 -8;并且有57分钟的中点睡眠，P = 5x 10 -7）。我们的研究结果表明，以前报道的孟德尔睡眠和昼夜节律条件的变异往往不是很高的渗透性时，偶然从一般人群中确定。临床上确定的以家庭为基础的研究先前已经确定了与导致终身睡眠条件相关的罕见遗传变异，特别是睡眠时间缩短以及睡眠时间提前或推迟。然而，先前报道的遗传变异对睡眠时间和时间的影响，当通过基于人群的研究偶然发现时，尚不清楚。在这里，我们利用来自四项基于人群的研究（包括英国生物银行）的多达191，929人，使用自我报告和基于加速度计的睡眠估计以及测序数据来估计这些变体对睡眠时间和时间的影响。我们的分析显示，先前报道的变异与极端睡眠条件之间没有关联。位于两个基因（PER 3和PER 11）中的两个变体显示出与睡眠时间相关的证据，但它们对睡眠时间的估计影响（约5至7分钟）相对于先前报道的要小得多。我们的研究结果表明，以前报道的变异不是一般人群极端睡眠条件的原因。最后，虽然我们无法分析先前报道的与睡眠时间相关的PER 2基因变异，但英国生物库的额外分析显示，与非携带者相比，该基因中的蛋白质截短变异携带者的睡眠中点提前了大约1小时。这些基于人口的估计很重要，因为最近直接面向消费者和卫生服务的全基因组基因检测急剧增加。
Rare variants in ten genes have been reported to cause Mendelian sleep conditions characterised by extreme sleep duration or timing. These include familial natural short sleep (ADRB1, DEC2/BHLHE41, GRM1 and NPSR1), advanced sleep phase (PER2, PER3, CRY2, CSNK1D and TIMELESS) and delayed sleep phase (CRY1). The association of variants in these genes with extreme sleep conditions were usually based on clinically ascertained families, and their effects when identified in the population are unknown. We aimed to determine the effects of these variants on sleep traits in large population-based cohorts. We performed genetic association analysis of variants previously reported to be causal for Mendelian sleep and circadian conditions. Analyses were performed using 191,929 individuals with data on sleep and whole-exome or genome-sequence data from 4 population-based studies: UK Biobank, FINRISK, Health-2000-2001, and the Multi-Ethnic Study of Atherosclerosis (MESA). We identified sleep disorders from self-report, hospital and primary care data. We estimated sleep duration and timing measures from self-report and accelerometery data. We identified carriers for 10 out of 12 previously reported pathogenic variants for 8 of the 10 genes. They ranged in frequency from 1 individual with the variant in CSNK1D to 1,574 individuals with a reported variant in the PER3 gene in the UK Biobank. No carriers for variants reported in NPSR1 or PER2 were identified. We found no association between variants analyzed and extreme sleep or circadian phenotypes. Using sleep timing as a proxy measure for sleep phase, only PER3 and CRY1 variants demonstrated association with earlier and later sleep timing, respectively; however, the magnitude of effect was smaller than previously reported (sleep midpoint ~7 mins earlier and ~5 mins later, respectively). We also performed burden tests of protein truncating (PTVs) or rare missense variants for the 10 genes. Only PTVs in PER2 and PER3 were associated with a relevant trait (for example, 64 individuals with a PTV in PER2 had an odds ratio of 4.4 for being “definitely a morning person”, P = 4x10-8; and had a 57-minute earlier midpoint sleep, P = 5x10-7). Our results indicate that previously reported variants for Mendelian sleep and circadian conditions are often not highly penetrant when ascertained incidentally from the general population. Clinically ascertained family-based studies have previously identified rare genetic variation associated with causing life-long sleep conditions, specifically shorter sleep, and earlier or later sleep timing. However, the effects of previously reported genetic variants on sleep duration and timing when identified incidentally through population-based studies are not known. Here, we take advantage of up to 191,929 individuals from four population-based studies, including the UK Biobank, to estimate the effects of these variants on sleep duration and timing using self-reported and accelerometer-based sleep estimates coupled with sequencing data. Our analysis revealed no association between variants previously reported and extreme sleep conditions. Two variants located in two genes (PER3 and CRY1) showed evidence of association with sleep timing, but their estimated effects (~5 to 7 minutes) on sleep timing are much smaller relative to those previously reported. Our results indicate that previously reported variants are not causal for extreme sleep conditions in the general population. Finally, although we were unable to analyse a previously reported variant in the PER2 gene associated with sleep timing, additional analysis in the UK Biobank revealed carries of protein-truncating variants in this gene have an approximately 1-hour earlier sleep midpoint compared to non-carriers. These population-based estimates are important because of the recent dramatic increase in direct-to-consumer and health service genome-wide genetic testing.
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影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
7.7
作者：
Borodulin, Katja;Tolonen, Hanna;Vartiainen, Erkki
通讯作者：
Vartiainen, Erkki
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
DOI：
10.1038/nrg2430
发表时间：
2008-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.6
作者：
Smieszek SP;Brzezynski JL;Kaden AR;Shinn JA;Wang J;Xiao C;Polymeropoulos C;Özçelik T;Polymeropoulos MH
通讯作者：
Polymeropoulos MH