Kripke Daniel F, Kline Lawrence E, Nievergelt Caroline M, Murray Sarah S, Shadan Farhad F, Dawson Arthur, Poceta J Steven, Cronin John, Jamil Shazia M, Tranah Gregory J, Loving Richard T, Grizas Alexandra P, Hahn Elizabeth K
Viterbi Family Sleep Center, Scripps Clinic, La Jolla, CA, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
Viterbi Family Sleep Center, Scripps Clinic, La Jolla, CA, USA.
Sleep Med. 2015 Feb;16(2):217-24. doi: 10.1016/j.sleep.2014.11.003. Epub 2014 Dec 5.
The diagnostic boundaries of sleep disorders are under considerable debate. The main sleep disorders are partly heritable; therefore, defining heritable pathophysiologic mechanisms could delineate diagnoses and suggest treatment. We collected clinical data and DNA from consenting patients scheduled to undergo clinical polysomnograms, to expand our understanding of the polymorphisms associated with the phenotypes of particular sleep disorders.
Patients at least 21 years of age were recruited to contribute research questionnaires, and to provide access to their medical records, saliva for deoxyribonucleic acid (DNA), and polysomnographic data. From these complex data, 38 partly overlapping phenotypes were derived indicating complaints, subjective and objective sleep timing, and polysomnographic disturbances. A custom chip was used to genotype 768 single-nucleotide polymorphisms (SNPs). Additional assays derived ancestry-informative markers (eg, 751 participants of European ancestry). Linear regressions controlling for age, gender, and ancestry were used to assess the associations of each phenotype with each of the SNPs, highlighting those with Bonferroni-corrected significance.
In peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B), rs6888451 was associated with several markers of obstructive sleep apnea. In aryl hydrocarbon receptor nuclear translocator-like (ARNTL), rs10766071 was associated with decreased polysomnographic sleep duration. The association of rs3923809 in BTBD9 with periodic limb movements in sleep was confirmed. SNPs in casein kinase 1 delta (CSNK1D rs11552085), cryptochrome 1 (CRY1 rs4964515), and retinoic acid receptor-related orphan receptor A (RORA rs11071547) were less persuasively associated with sleep latency and time of falling asleep.
SNPs associated with several sleep phenotypes were suggested, but due to risks of false discovery, independent replications are needed before the importance of these associations can be assessed, followed by investigation of molecular mechanisms.
睡眠障碍的诊断界限存在相当大的争议。主要睡眠障碍部分具有遗传性；因此，确定遗传性病理生理机制可以明确诊断并为治疗提供建议。我们收集了同意接受临床多导睡眠图检查的患者的临床数据和DNA，以加深我们对与特定睡眠障碍表型相关的多态性的理解。
招募年龄至少21岁的患者填写研究问卷，并提供其病历、用于脱氧核糖核酸（DNA）检测的唾液以及多导睡眠图数据。从这些复杂数据中得出38种部分重叠的表型，表明症状、主观和客观睡眠时间以及多导睡眠图干扰情况。使用定制芯片对768个单核苷酸多态性（SNP）进行基因分型。另外的检测得出祖先信息标记（例如，751名欧洲血统参与者）。使用控制年龄、性别和祖先的线性回归来评估每种表型与每个SNP之间的关联，突出显示经Bonferroni校正具有显著性的关联。
在过氧化物酶体增殖物激活受体γ共激活因子1β（PPARGC1B）中，rs6888451与阻塞性睡眠呼吸暂停的几个标志物相关。在芳烃受体核转运蛋白样蛋白（ARNTL）中，rs10766071与多导睡眠图记录的睡眠时间缩短相关。BTBD9中rs3923809与睡眠周期性肢体运动的关联得到证实。酪蛋白激酶1δ（CSNK1D rs11552085）、隐花色素1（CRY1 rs4964515）和视黄酸受体相关孤儿受体A（RORA rs11071547）中的SNP与睡眠潜伏期和入睡时间的关联不太有说服力。
提出了与几种睡眠表型相关的SNP，但由于存在错误发现的风险，在评估这些关联的重要性之前需要进行独立复制，随后再研究分子机制。
