Association of peripheral blood DNA methylation level with Alzheimer's disease progression.
Association of peripheral blood DNA methylation level with Alzheimer's disease progression.
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DOI：
10.1186/s13148-021-01179-2
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发表时间：
2021-10-15
影响因子：
5.7
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
中科院分区：
文献类型：
--
作者：
Li QS;Vasanthakumar A;Davis JW;Idler KB;Nho K;Waring JF;Saykin AJ;Alzheimer’s Disease Neuroimaging Initiative (ADNI)
识别与阿尔茨海默病（AD）进展相关的生物标志物可以使患者富集并改善临床试验设计。表观基因组关联研究揭示了胞嘧啶-磷酸-鸟嘌呤（CpG）位点的DNA甲基化与AD病理学和诊断之间的相关性。在这里，我们报告了使用Infinium® MethylationEPIC BeadChip测量的外周血DNA甲基化谱与阿尔茨海默病神经影像学倡议（ADNI）队列参与者的AD进展之间的关系。分别在认知正常（CN）受试者和轻度认知障碍（MCI）患者中，使用稳健线性回归，通过改良的临床前阿尔茨海默氏症认知复合量表（mPACC; mPACCdigit和mPACCtrailsB）和临床痴呆评定量表方框总和（CDR-SB）图的斜率，估计从初始DNA采样访视到后续访视的认知下降率。此外，使用二分终点评估诊断转换状态。两个CpG位点与CN受试者的mPACC斜率显著相关（P < 5.79 × 10−8 [Bonferroni校正阈值]）; cg 00386386与mPACC数字斜率相关，注释到RP 11 -661A12.5的cg 09422696与CDR-SB斜率相关。未发现与诊断转换状态相关的显著CpG位点。参与认知和学习的基因得到了丰富。通过comb-p和DMRcate算法分别鉴定了与mPACCtrailsB、mPACCdigit和CDR-SB斜率相关的总共19、13和5个差异甲基化区域（DMR）;这些包括注释为HOXA 4的DMR。此外，分别有5和19例DMR与CN和MCI参与者的转换状态相关。最显著的DMR注释为AD相关基因PM20 D1（chr 1：205，818，956至205，820，014 [13个探针]，Sidak校正P = 7.74 × 10−24），其与CDR-SB的斜率和MCI转换状态相关。外周血中的候选CpG位点和区域被确定为与ADNI队列中参与者的认知下降率相关。虽然由于观察到的效应大小，我们没有鉴定出具有足够临床实用性的单个CpG位点，但由DNA甲基化变化组成的生物特征可能具有作为AD进展的预后生物标志物的实用性。在线版本包含补充材料，可通过10.1186/s13148-021-01179-2获得。
Identifying biomarkers associated with Alzheimer’s disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome-wide association studies have revealed correlations between DNA methylation at cytosine-phosphate-guanine (CpG) sites and AD pathology and diagnosis. Here, we report relationships between peripheral blood DNA methylation profiles measured using Infinium® MethylationEPIC BeadChip and AD progression in participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. The rate of cognitive decline from initial DNA sampling visit to subsequent visits was estimated by the slopes of the modified Preclinical Alzheimer Cognitive Composite (mPACC; mPACCdigit and mPACCtrailsB) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) plots using robust linear regression in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI), respectively. In addition, diagnosis conversion status was assessed using a dichotomized endpoint. Two CpG sites were significantly associated with the slope of mPACC in CN participants (P < 5.79 × 10−8 [Bonferroni correction threshold]); cg00386386 was associated with the slope of mPACCdigit, and cg09422696 annotated to RP11-661A12.5 was associated with the slope of CDR-SB. No significant CpG sites associated with diagnosis conversion status were identified. Genes involved in cognition and learning were enriched. A total of 19, 13, and 5 differentially methylated regions (DMRs) associated with the slopes of mPACCtrailsB, mPACCdigit, and CDR-SB, respectively, were identified by both comb-p and DMRcate algorithms; these included DMRs annotated to HOXA4. Furthermore, 5 and 19 DMRs were associated with conversion status in CN and MCI participants, respectively. The most significant DMR was annotated to the AD-associated gene PM20D1 (chr1: 205,818,956 to 205,820,014 [13 probes], Sidak-corrected P = 7.74 × 10−24), which was associated with both the slope of CDR-SB and the MCI conversion status. Candidate CpG sites and regions in peripheral blood were identified as associated with the rate of cognitive decline in participants in the ADNI cohort. While we did not identify a single CpG site with sufficient clinical utility to be used by itself due to the observed effect size, a biosignature composed of DNA methylation changes may have utility as a prognostic biomarker for AD progression. The online version contains supplementary material available at 10.1186/s13148-021-01179-2.
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影响因子：
29
作者：
Donohue, Michael C.;Sperling, Reisa A.;Salmon, David P.;Rentz, Dorene M.;Raman, Rema;Thomas, Ronald G.;Weiner, Michael;Aisen, Paul S.
通讯作者：
Aisen, Paul S.
影响因子：
3.6
作者：
Bencze J;Mórotz GM;Seo W;Bencs V;Kálmán J;Miller CCJ;Hortobágyi T
通讯作者：
Hortobágyi T
影响因子：
3.7
作者：
Beltran, Juan Felipe;Wahba, Brandon Malik;Kline, Richard P.
通讯作者：
Kline, Richard P.
影响因子：
3.5
作者：
Evangelisti, C.;Bianco, F.;Bonora, E.
通讯作者：
Bonora, E.
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK