Division of Sleep Medicine/Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 125 S. 31st St, Office 2123, Philadelphia, PA, 19104, USA.
Sleep Disorders Division/Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
BMC Med Genomics. 2020 Jul 25;13(1):105. doi: 10.1186/s12920-020-00755-4.
Obstructive sleep apnea (OSA) is defined by frequent episodes of reduced or complete cessation of airflow during sleep and is linked to negative health outcomes. Understanding the genetic factors influencing expression of OSA may lead to new treatment strategies. Electronic health records (EHRs) can be leveraged to both validate previously reported OSA-associated genomic variation and detect novel relationships between these variants and comorbidities.
We identified candidate single nucleotide polymorphisms (SNPs) via systematic literature review of existing research. Using datasets available at Geisinger (n = 39,407) and Vanderbilt University Medical Center (n = 24,084), we evaluated associations between 40 previously implicated SNPs and OSA diagnosis, defined using clinical codes. We also evaluated associations between these SNPs and OSA severity measures obtained from sleep reports at Geisinger (n = 6571). Finally, we used a phenome-wide association study approach to help reveal pleiotropic genetic effects between OSA candidate SNPs and other clinical codes and laboratory values available in the EHR.
Most previously reported OSA candidate SNPs showed minimal to no evidence for associations with OSA diagnosis or severity in the EHR-derived datasets. Three SNPs in LEPR, MMP-9, and GABBR1 validated for an association with OSA diagnosis in European Americans; the SNP in GABBR1 was associated following meta-analysis of results from both clinical populations. The GABBR1 and LEPR SNPs, and one additional SNP, were associated with OSA severity measures in European Americans from Geisinger. Three additional candidate OSA SNPs were not associated with OSA-related traits but instead with hyperlipidemia and autoimmune diseases of the thyroid.
To our knowledge, this is one of the largest candidate gene studies and one of the first phenome-wide association studies of OSA genomic variation. Results validate genetic associates with OSA in the LEPR, MMP-9 and GABBR1 genes, but suggest that the majority of previously identified genetic associations with OSA may be false positives. Phenome-wide analyses provide evidence of mediated pleiotropy. Future well-powered genome-wide association analyses of OSA risk and severity across populations with diverse ancestral backgrounds are needed. The comprehensive nature of the analyses represents a platform for informing future work focused on understanding how genetic data can be useful to informing treatment of OSA and related comorbidities.
阻塞性睡眠呼吸暂停（OSA）是指睡眠期间气流频繁减少或完全停止的病症，与负面健康结果相关。了解影响 OSA 表达的遗传因素可能会带来新的治疗策略。电子健康记录（EHR）可用于验证先前报告的 OSA 相关基因组变异，并发现这些变体与合并症之间的新关系。
我们通过系统地回顾现有研究文献，确定了候选单核苷酸多态性（SNP）。使用 Geisinger（n=39407）和范德比尔特大学医学中心（n=24084）的数据集，我们评估了 40 个先前涉及的 SNP 与使用临床代码定义的 OSA 诊断之间的关联。我们还评估了这些 SNP 与从 Geisinger 的睡眠报告中获得的 OSA 严重程度测量值之间的关联（n=6571）。最后，我们使用表型全基因组关联研究方法来帮助揭示 OSA 候选 SNP 与 EHR 中其他临床代码和实验室值之间的多效遗传效应。
大多数先前报告的 OSA 候选 SNP 在 EHR 衍生数据集中与 OSA 诊断或严重程度几乎没有关联。在欧洲裔美国人中，LEPR、MMP-9 和 GABBR1 中的三个 SNP 验证与 OSA 诊断相关；在对来自两个临床人群的结果进行荟萃分析后，GABBR1 中的 SNP 也与 OSA 诊断相关。在欧洲裔美国人中，GABBR1 和 LEPR 中的 SNP 以及另外一个 SNP 与 OSA 严重程度测量值相关。另外三个候选 OSA SNP 与 OSA 相关特征无关，但与血脂异常和甲状腺自身免疫性疾病相关。
据我们所知，这是最大的候选基因研究之一，也是 OSA 基因组变异的首个表型全基因组关联研究之一。结果验证了 LEPR、MMP-9 和 GABBR1 基因中与 OSA 相关的遗传因素，但表明大多数先前确定的与 OSA 相关的遗传关联可能是假阳性。表型全基因组分析提供了介导的多效性的证据。需要在具有不同祖先背景的人群中进行针对 OSA 风险和严重程度的全基因组关联分析。分析的全面性代表了一个平台，可以为未来的工作提供信息，重点是了解如何利用遗传数据为 OSA 及相关合并症的治疗提供信息。
