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Background/Aims: We conducted the first large-scale epigenome-wide meta-analysis of brain structure, integrating blood DNA methylation (DNAm) and MRI data from 4,925 individuals of European ancestry, with replication in independent samples comprising 2,563 participants of European and other ancestries. Epigenome-wide association studies identified 31 CpG sites associated with average cortical thickness (CT) and 12 with total cortical surface area (SA; PFDR < 0.05), implicating genes involved in neurodevelopment, inflammation, and environmental exposures. Four CT-related CpG (cytosine–phosphate–guanine) sites replicated, and were functionally linked to altered gene expression across brain and peripheral tissues.
Conclusions: Differentially methylated regions (DMRs), particularly at 17q21.31 (KANSL1, ARHGAP27), were strongly associated with SA. Mendelian randomisation analyses supported causal roles for several DMR-associated CpGs in shaping cortical morphology and influencing risk for schizophrenia, bipolar disorder, Alzheimer’s disease, and lower educational attainment. Methylation profile scores a modest proportion of SA variance (0.76%) but not CT in an independent cohort. These findings highlight biologically relevant DNAm signatures of cortical morphology, support their relevance to psychiatric outcomes, and position blood DNAm as a potential biomarker of brain health.