Brueggeman Leo, Pottschmidt Natalie, Koomar Tanner, Thomas Taylor, Michaelson Jacob J
Department of Psychiatry, University of Iowa, Iowa City, USA.
Department of Psychology, Pennsylvania State University, State College, USA.
medRxiv. 2025 Apr 6:2025.04.04.25325272. doi: 10.1101/2025.04.04.25325272.
Poor sleep is a major concern among individuals with autism and their caregivers. To better characterize the genetic and phenotypic heterogeneity of poor sleep in autism, we recruited 5,686 families from SPARK, a nationwide genetic study of autism, who described their sleep experiences using the Children's Sleep Health Questionnaire (CSHQ) and other self-report items. The collective experiences from this large sample allowed us to discover eight distinct archetypes of sleep in autism. Membership in some of these archetypes showed significant SNP-heritability (0.50 - 0.65, 95% confidence interval = 0.08 - 1), and polygenic estimates of educational attainment, BMI, and ADHD risk contributed extensively to the genetic signatures of these sleep archetypes. Surprisingly, polygenic estimates of general population sleep phenotypes showed sparser and more modest associations, perhaps suggesting that the genetic drivers of disordered sleep in autism may be distinct from those encountered in the general population. GWAS on archetype membership yielded no genome-wide significant loci, however, the most significant gene for the most severe archetype was the nitric oxide (NO) signaling gene , which was previously linked to sleep disruption in schizophrenia. Finally, the eight sleep archetypes showed specific signatures of treatment response across five major categories of sleep aid, pointing to the potential of treatment plans that are tailored to the nature of the sleep problem. These findings provide critical new insight into the comorbidities, subtypes, and genetic risk factors associated with disordered sleep in autism.
睡眠质量差是自闭症患者及其照顾者主要关注的问题。为了更好地描述自闭症患者睡眠质量差的遗传和表型异质性，我们从自闭症全国性基因研究项目SPARK中招募了5686个家庭，这些家庭使用儿童睡眠健康问卷（CSHQ）和其他自我报告项目描述了他们的睡眠经历。这个大样本的综合经历使我们发现了自闭症患者睡眠的八种不同原型。其中一些原型的成员表现出显著的单核苷酸多态性遗传力（0.50 - 0.65，95%置信区间 = 0.08 - 1），并且教育程度、体重指数和注意力缺陷多动障碍风险的多基因估计对这些睡眠原型的基因特征有很大贡献。令人惊讶的是，一般人群睡眠表型的多基因估计显示出更稀疏、更适度的关联，这可能表明自闭症患者睡眠紊乱的遗传驱动因素可能与一般人群中遇到的不同。对原型成员的全基因组关联研究（GWAS）没有产生全基因组显著位点，然而，最严重原型中最显著的基因是一氧化氮（NO）信号基因，该基因先前与精神分裂症的睡眠中断有关。最后，这八种睡眠原型在五类主要助眠药物中显示出特定的治疗反应特征，这表明针对睡眠问题性质量身定制治疗方案具有潜力。这些发现为与自闭症患者睡眠紊乱相关的共病、亚型和遗传风险因素提供了重要的新见解。
