SCZ_MWAS_meta_analysis_GSE80417_GSE152027_GSE84727.csv

Objective: This study sought to determine if the R package LDpred2, designed for polygenic risk score creation for genome-wide association studies using summary statistics, could be adapted for deriving DNA methylation scores from methylome-wide association studies. Recognizing that linkage disequilibrium, used as prior in LDpred2, does not apply to methylation, we explored co-methylated regions and topologically associating domains as alternative structural priors for correlation between methylation sites. A genomic sliding-window approach was also tested. The performance of the LDpred2-based models was evaluated on methylation data from schizophrenia and control samples (N=1,227). Results: LDpred2 models employing topologically associating domains and sliding window clusters as priors performed similarly to existing methods, explaining approximately 3.6% of schizophrenia phenotypic variance. The co-methylated regions model underperformed due to insufficient clustering of probes. The similarity in performance between the model using topologically associating domains and a null model consisting of random clusters suggests that the structural information provided by these domains enhances performance only marginally. In conclusion, while LDpred2 can be adapted for methylation data, it does not substantially enhance methylation score performance over existing methods, and the choice of structural prior may not be a critical factor .

研究目的：本研究旨在探究专为利用汇总统计量开展全基因组关联研究（genome-wide association studies, GWAS）构建多基因风险评分而设计的R包LDpred2，是否可适配用于从甲基化组全关联研究（methylome-wide association studies, MWAS）中推导DNA甲基化评分。鉴于LDpred2中作为先验信息使用的连锁不平衡（linkage disequilibrium, LD）并不适用于甲基化数据，本研究探索了共甲基化区域与拓扑关联域（topologically associating domains）作为甲基化位点间相关性的替代结构性先验，并测试了基因组滑动窗口方法。基于LDpred2的模型性能通过样本量为1227的精神分裂症患者与对照样本的甲基化数据进行评估。研究结果：以拓扑关联域和滑动窗口聚类作为先验的LDpred2模型性能与现有方法相当，可解释约3.6%的精神分裂症表型变异。共甲基化区域模型因探针聚类不足而表现欠佳。以拓扑关联域构建的模型与随机聚类的零模型性能相近，表明这些结构域提供的结构信息仅能小幅提升模型性能。研究结论：综上，尽管LDpred2可适配甲基化组数据，但其并未在现有方法基础上显著提升甲基化评分的性能，且结构性先验的选择或许并非关键影响因素。