Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Center for Genomic Medicine, Massachusetts General Hospital, Boston.
JAMA Psychiatry. 2021 Aug 1;78(8):903-910. doi: 10.1001/jamapsychiatry.2021.0959.
Morning diurnal preference is associated with reduced risk of major depressive disorder (MDD); however, causality in this association is uncertain.
To examine the association of genetically proxied morning diurnal preference with depression risk using mendelian randomization.
DESIGN, SETTING, AND PARTICIPANTS: This 2-sample mendelian randomization study used summary-level genetic associations with diurnal preference and MDD. Up to 340 genetic loci associated with diurnal preference in a meta-analysis of the UK Biobank and 23andMe cohorts were considered as genetic proxies for diurnal preference. The effect size of these variants was scaled using genetic associations with accelerometer-based measurement of sleep midpoint. Genetic associations with MDD were obtained from a meta-analysis of genome-wide association studies data from the Psychiatric Genomics Consortium and UK Biobank. The inverse-variance weighted method was used to estimate the association of genetically proxied morning diurnal preference, corresponding to a 1-hour earlier sleep midpoint, with MDD risk.
Morning diurnal preference scaled to a 1-hour earlier, objectively measured sleep midpoint.
Risk of MDD, including self-reported and clinically diagnosed cases, as ascertained in meta-analyses of genome-wide association studies.
A total of 697 828 individuals (all of European ancestry) were in the UK Biobank and 23andMe cohorts; 85 502 in the UK Biobank had measurements of the sleep midpoint. A further 170 756 individuals with MDD and 329 443 control participants (all of European ancestry) were in the Psychiatric Genomics Consortium and UK Biobank data. Genetically proxied earlier diurnal preference was associated with a 23% lower risk of depression (odds ratio [OR] per 1-hour earlier sleep midpoint, 0.77 [95% CI, 0.63-0.94]; P = .01). This association was similar when restricting analysis to individuals with MDD as stringently defined by the Psychiatric Genomics Consortium (OR, 0.73 [95% CI, 0.54-1.00]; P = .05) but not statistically significant when defined by hospital-based billing codes in the UK Biobank (OR, 0.64 [95% CI, 0.39-1.06]; P = .08). Sensitivity analyses examining potential bias due to pleiotropy or reverse causality showed similar findings (eg, intercept [SE], 0.00 [0.001]; P = .66 by Egger intercept test).
The results of this mendelian randomization study support a protective association of earlier diurnal preference with risk of MDD and provide estimates contextualized to an objective sleep timing measure. Further investigation in the form of randomized clinical trials may be warranted.
晨型偏好与降低重度抑郁症（MDD）风险有关；然而，这种关联的因果关系尚不确定。
使用孟德尔随机化研究遗传上接近的晨型偏好与抑郁风险之间的关联。
设计、设置和参与者：这项两样本孟德尔随机化研究使用了与昼夜节律偏好和 MDD 相关的汇总水平遗传关联。在英国生物库和 23andMe 队列的荟萃分析中，与昼夜节律偏好相关的多达 340 个遗传位点被认为是昼夜节律偏好的遗传替代物。这些变体的效应大小是通过遗传关联使用基于加速度计的睡眠中点测量来缩放的。MDD 的遗传关联是从精神病学基因组学联盟和英国生物库的全基因组关联研究荟萃分析中获得的。使用逆方差加权法估计遗传上接近的晨型偏好（对应于睡眠中点提前 1 小时）与 MDD 风险之间的关联，睡眠中点是通过基于加速度计的测量获得的。
晨型偏好，调整为睡眠中点提前 1 小时，这是一种客观的测量方法。
MDD 风险，包括全基因组关联研究荟萃分析中确定的自我报告和临床诊断病例。
共有 697828 名（均为欧洲血统）个体纳入英国生物库和 23andMe 队列；85502 名个体在英国生物库中测量了睡眠中点。另外，170756 名 MDD 患者和 329443 名对照参与者（均为欧洲血统）纳入精神病学基因组学联盟和英国生物库的数据。遗传上接近的更早的昼夜节律偏好与抑郁风险降低 23%相关（每提前 1 小时睡眠中点的优势比[OR]，0.77[95%CI，0.63-0.94]；P=0.01）。当将分析限制在精神病学基因组学联盟严格定义的 MDD 患者中时，这种关联相似（OR，0.73[95%CI，0.54-1.00]；P=0.05），但在英国生物库中基于医院计费代码定义时无统计学意义（OR，0.64[95%CI，0.39-1.06]；P=0.08）。对潜在的由于多效性或反向因果关系引起的偏差进行敏感性分析的结果相似（例如，截距[SE]，0.00[0.001]；Egger 截距检验 P=0.66）。
这项孟德尔随机化研究的结果支持更早的昼夜节律偏好与 MDD 风险之间存在保护性关联，并提供了与客观睡眠时间测量相关的估计。可能需要进一步的以随机临床试验形式进行研究。
