PDF(Pubmed)
Abstract：
BACKGROUND: The study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex.
RESULTS: We found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific and nonlinear age effects that differed between clocks and point to possible distinct age windows of altered aging in SCZ. Most notably, intrinsic cellular age (Horvath clock) is decelerated in SCZ cases in young adulthood, while phenotypic age (Levine clock) is accelerated in later adulthood compared to controls. Accelerated phenotypic aging was most pronounced in women with SCZ carrying a high polygenic burden with an age acceleration of + 3.82 years (CI 2.02-5.61, P = 1.1E-03). Phenotypic aging and SCZ polygenic risk contributed additively to the illness and together explained up to 14.38% of the variance in disease status.
CONCLUSIONS: Our study contributes to the growing body of evidence of altered DNAm aging in SCZ and points to intrinsic age deceleration in younger adulthood and phenotypic age acceleration in later adulthood in SCZ. Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. Our study did not find that DNAm aging could be explained by the duration of illness of patients, but we did observe age- and sex-specific effects that warrant further investigation. Finally, our results show that combining genetic and epigenetic predictors can improve predictions of disease outcomes and may help with disease management in schizophrenia.
RESULTS: We found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific and nonlinear age effects that differed between clocks and point to possible distinct age windows of altered aging in SCZ. Most notably, intrinsic cellular age (Horvath clock) is decelerated in SCZ cases in young adulthood, while phenotypic age (Levine clock) is accelerated in later adulthood compared to controls. Accelerated phenotypic aging was most pronounced in women with SCZ carrying a high polygenic burden with an age acceleration of + 3.82 years (CI 2.02-5.61, P = 1.1E-03). Phenotypic aging and SCZ polygenic risk contributed additively to the illness and together explained up to 14.38% of the variance in disease status.
CONCLUSIONS: Our study contributes to the growing body of evidence of altered DNAm aging in SCZ and points to intrinsic age deceleration in younger adulthood and phenotypic age acceleration in later adulthood in SCZ. Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. Our study did not find that DNAm aging could be explained by the duration of illness of patients, but we did observe age- and sex-specific effects that warrant further investigation. Finally, our results show that combining genetic and epigenetic predictors can improve predictions of disease outcomes and may help with disease management in schizophrenia.
摘要：
背景：对生物学年龄加速的研究可能有助于识别有风险的个体，并减少与年龄相关的疾病的全球负担。使用DNA甲基化（DNAm）时钟，我们调查了精神分裂症（SCZ）的生物衰老，与年龄相关的残疾和发病率增加相关的精神疾病。在四个欧洲队列的1090个SCZ病例和1206个对照的全血DNAm样本中，我们使用三个DNAm时钟对差分老化进行了荟萃分析(即，汉纳姆,Horvath,和Levine）。为了剖析DNAm老化如何影响SCZ，我们整合了疾病持续时间和SCZ多基因风险的信息，以及按实际年龄和生物性别对我们的分析进行分层。
结果：我们发现SCZ中基于血液的DNAm老化显著改变，与发病后的病程无关。我们观察到特定性别和非线性的年龄效应在时钟之间有所不同，并指出SCZ中可能发生不同年龄的年龄窗口。最值得注意的是,在年轻的成年期SCZ病例中，固有细胞年龄（Horvath时钟）减速，与对照组相比，表型年龄（Levine时钟）在成年后期加速。在SCZ携带高多基因负担的女性中，表型老化加速最为明显，年龄加速为3.82岁（CI2.02-5.61，P=1.1E-03）。表型老化和SCZ多基因风险对疾病有额外的贡献，并共同解释了高达14.38％的疾病状态差异。
结论：我们的研究有助于SCZ中DNAm老化改变的证据越来越多，并指出SCZ中年轻成年期的内在年龄减速和成年后期的表型年龄加速。由于表型年龄的增加与全因死亡风险的增加有关，我们的研究结果表明,通过Levine时钟测量,特定和可识别的患者组的死亡风险增加.我们的研究没有发现DNAm老化可以用患者的疾病持续时间来解释，但我们确实观察到了需要进一步调查的年龄和性别特异性效应.最后,我们的研究结果表明,结合遗传和表观遗传预测因子可以改善对疾病结局的预测,并可能有助于精神分裂症的疾病管理.
结果：我们发现SCZ中基于血液的DNAm老化显著改变，与发病后的病程无关。我们观察到特定性别和非线性的年龄效应在时钟之间有所不同，并指出SCZ中可能发生不同年龄的年龄窗口。最值得注意的是,在年轻的成年期SCZ病例中，固有细胞年龄（Horvath时钟）减速，与对照组相比，表型年龄（Levine时钟）在成年后期加速。在SCZ携带高多基因负担的女性中，表型老化加速最为明显，年龄加速为3.82岁（CI2.02-5.61，P=1.1E-03）。表型老化和SCZ多基因风险对疾病有额外的贡献，并共同解释了高达14.38％的疾病状态差异。
结论：我们的研究有助于SCZ中DNAm老化改变的证据越来越多，并指出SCZ中年轻成年期的内在年龄减速和成年后期的表型年龄加速。由于表型年龄的增加与全因死亡风险的增加有关，我们的研究结果表明,通过Levine时钟测量,特定和可识别的患者组的死亡风险增加.我们的研究没有发现DNAm老化可以用患者的疾病持续时间来解释，但我们确实观察到了需要进一步调查的年龄和性别特异性效应.最后,我们的研究结果表明,结合遗传和表观遗传预测因子可以改善对疾病结局的预测,并可能有助于精神分裂症的疾病管理.
