HERITABILITY OF SLEEP HOMEOSTASIS

白天过度嗜睡是我们社会的一个普遍问题，与车祸和工业事故的风险增加有关。嗜睡在一定程度上是由与睡眠稳态有关的基本生物学决定的，即清醒时睡眠压力的累积速度。据报道，睡眠剥夺的易感性在正常受试者中存在差异，这些受试者在相同的睡眠时间内产生的功能损害程度存在很大的个体差异。最近对近交系小鼠的研究表明，遗传学可能在睡眠稳态中发挥重要作用，但遗传学是否在人类中发挥作用，如果是的话，这种作用的大小尚不清楚。这项建议是 基于睡眠动态平衡是人类可遗传特征的假设。鉴于表型研究睡眠稳态的复杂性，我们认为研究同卵双胞胎和异卵双胞胎表型变异的差异是估计睡眠稳态遗传力的最佳方法。我们将对80对同卵双胞胎和80对异卵双胞胎的睡眠动态平衡进行评估，方法是量化睡眠剥夺后恢复睡眠期间Delta功率的增加，以及在长时间清醒期间theta功率的增加。受试者将通过彭尼双胞胎队列招募，这是一个以人口为基础的队列，约有1800对双胞胎。如果显示出睡眠稳态的遗传性， 这种基于脑电的表型策略不能轻易地应用于评估潜在遗传变异所需的更大规模的人群研究。因此，我们总体战略的一部分是评估并潜在地验证其他表型鉴定方法，这些方法在生理上不那么严格，但更容易应用于更多的受试者。因此，作为一个辅助目标，我们还将估计在长时间清醒期间表现下降的遗传率，作为评估睡眠稳态的替代方法。我们将特别确定双卵双胞胎之间基于我们的生理密集表型的测量方法的差异是否反映在这种更容易执行的表型方法的差异中。这样的结果将表明，这种更简单的方法可以用于更大规模的人口研究，并将成为未来阐明决定嗜睡的基因变异的策略的一部分。

Excessive daytime sleepiness is a prevalent problem in our society associated with an increased risk of vehicular crashes and industrial accidents. Sleepiness is, in part, determined by fundamental biology relating to sleep homeostasis, i.e., the rate of accumulation of the pressure for sleep during wakefulness. A differential susceptibility to sleep deprivation is reported in normal subjects with large intra-individual differences in the degree of functional impairment produced by the same duration of sleep. Genetics are likely to play an important role in sleep homeostasis as shown by recent studies in inbred mouse strains, but whether genetics plays any role in humans and, if so, the magnitude of this role, is unknown. This proposal is based on the hypothesis that sleep homeostasis is a heritable trait in humans. Given the complexity of phenotyping to study sleep homeostasis, we propose that studying differences in the variances of the phenotype between monozygotic and dizygotic twins is the optimal approach to estimate heritability of sleep homeostasis. We will assess sleep homeostasis in 80 pairs of monozygotic and 80 pairs of dizygotic twins by quantifying the increase in delta power during recovery sleep following sleep deprivation and the increase in theta power during the period of prolonged wakefulness. Subjects will be recruited using the PennTwins Cohort, a population-based cohort of about 1,800 twin pairs. If heritability of sleep homeostasis is shown, this EEG-based phenotyping strategy could not be easily applied to the larger scale population studies that will be required to assess underlying genetic variants. Thus, part of our overall strategy is to evaluate, and potentially validate, other approaches to phenotyping that are less physiologically rigorous but are more easily applied to a larger number of subjects. Therefore, as a subsidiary goal, we will also estimate heritability of performance lapses during prolonged wakefulness as a surrogate method to assess sleep homeostasis. We will particularly determine whether the differences in the measures based on our physiological intensive phenotypes between pairs of dizygotic twins are reflected in differences in this phenotyping approach that is simpler to perform. Such a result would indicate that this simpler method could be used in larger scale population studies, and will be part of future strategies to elucidate genetic variants determining sleepiness.