Polygenic risk score identifies associations between sleep duration and diseases determined from an electronic medical record biobank
Polygenic risk score identifies associations between sleep duration and diseases determined from an electronic medical record biobank
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DOI：
10.1093/sleep/zsy247
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发表时间：
2019-03-01
期刊：
影响因子：
5.6
通讯作者：
Saxena, Richa
中科院分区：
文献类型：
--
作者：
Dashti, Hassan S.;Redline, Susan;Saxena, Richa
研究目的：利用伙伴生物库(Partners Biobank)--一项将电子病历(EMR)与遗传信息联系起来的医院队列研究--检测睡眠时间与流行疾病之间的横断面表型和多基因风险评分(Polygenic Risk Score，PRS)。使用来自全基因组关联研究的78个先前相关的单核苷酸多态(SNP)得出了关于睡眠持续时间的PRS。我们测试了(1)自述睡眠时间与22种常见病(n=30251)、(2)自述睡眠与自述睡眠时间(n=6903)、(3)自述睡眠与22种常见病(n=16033)之间的关系。结果在年龄、性别和种族调整的模型中，观察到睡眠时间与哮喘、抑郁、高血压、失眠、肥胖、阻塞性睡眠呼吸暂停和2型糖尿病之间的U型关联，其中短睡眠者和长睡眠者患这些疾病的几率都高于正常睡眠者(p<；2.27 x 10(-3))。接下来，我们证实了PR与较长睡眠时间之间的关联(每个效应等位基因0.65~0.19 SD分钟；p=7.32 x 10(-04))。共解释了1.4%的睡眠时间表型变异。在调整了年龄、性别、基因分型排列和祖先的主要成分后，我们观察到，PRS还与充血性心力衰竭(p=0.015)、肥胖(p=0.019)、高血压(p=0.039)、不宁腿综合征(rls；p=0.041)和失眠(p=0.049)相关。在对肥胖状况进行额外调整后，除高血压和失眠外，其他相关因素保持不变。对于除RLS以外的所有疾病，携带较高遗传负担的78个睡眠持续时间增加的等位基因(即较高的睡眠持续时间PR)与较低的流行疾病几率相关。在MR中，我们估计了基因定义的较长睡眠时间与CHF风险降低(倒方差加权[IVW]或每分钟睡眠[95%CI]=0.978[0.961-0.996]；p=0.019)和高血压(IVW OR[95%CI]=0.993[0.986-1.000]；p=0.049)和RLS风险增加(IVW OR[95%CI]=1.018[1.000-1.036]；P=0.045)。结论通过验证睡眠持续时间和识别跨表型关联，我们为未来使用大型电子病历数据集研究睡眠、遗传学、临床测量和疾病之间的交集奠定了基础。
Study Objectives We aimed to detect cross-sectional phenotype and polygenic risk score (PRS) associations between sleep duration and prevalent diseases using the Partners Biobank, a hospital-based cohort study linking electronic medical records (EMR) with genetic information.Methods Disease prevalence was determined from EMR, and sleep duration was self-reported. A PRS for sleep duration was derived using 78 previously associated SNPs from genome-wide association studies (GWAS) for self-reported sleep duration. We tested for associations between (1) self-reported sleep duration and 22 prevalent diseases (n = 30251), (2) the PRS and self-reported sleep duration (n = 6903), and (3) the PRS and the 22 prevalent diseases (n = 16033). For observed PRS-disease associations, we tested causality using two-sample Mendelian randomization (MR).Results In the age-, sex-, and race-adjusted model, U-shaped associations were observed for sleep duration and asthma, depression, hypertension, insomnia, obesity, obstructive sleep apnea, and type 2 diabetes, where both short and long sleepers had higher odds for these diseases than normal sleepers (p < 2.27 x 10(-3)). Next, we confirmed associations between the PRS and longer sleep duration (0.65 0.19 SD minutes per effect allele; p = 7.32 x 10(-04)). The PRS collectively explained 1.4% of the phenotypic variance in sleep duration. After adjusting for age, sex, genotyping array, and principal components of ancestry, we observed that the PRS was also associated with congestive heart failure (CHF; p = 0.015), obesity (p = 0.019), hypertension (p = 0.039), restless legs syndrome (RLS; p = 0.041), and insomnia (p = 0.049). Associations were maintained following additional adjustment for obesity status, except for hypertension and insomnia. For all diseases, except RLS, carrying a higher genetic burden of the 78 sleep duration-increasing alleles (i.e. higher sleep duration PRS) associated with lower odds for prevalent disease. In MR, we estimated causal associations between genetically defined longer sleep duration with decreased risk of CHF (inverse variance weighted [IVW] OR per minute of sleep [95% CI] = 0.978 [0.961-0.996]; p = 0.019) and hypertension (IVW OR [95% CI] = 0.993 [0.986-1.000]; p = 0.049), and increased risk of RLS (IVW OR [95% CI] = 1.018 [1.000-1.036]; p = 0.045).Conclusions By validating the PRS for sleep duration and identifying cross-phenotype associations, we lay the groundwork for future investigations on the intersection between sleep, genetics, clinical measures, and diseases using large EMR datasets.