DNA methylation signatures associated with early-onset schizophrenia in Chinese patients

Schizophrenia is a heterogeneous psychiatric disorder with diverse clinical manifestations and complex biological mechanisms, in which age-at-onset (AAO) critically influences disease trajectory. Patients with early-onset schizophrenia (EOS; AAO < 18 years) present with more pronounced neurodevelopmental deficits and poorer long-term outcomes compared to adult-onset (AOS) cases. Previous genetic research on AAO and EOS has primarily focused on candidate genes and genome-wide association studies (GWAS). DNA methylation, an epigenetic mechanism influenced by the interplay between environmental and genetic factors, remains understudied, especially in the Chinese population. Peripheral blood DNA from 120 schizophrenia patients (49 EOS, 71 AOS) was analyzed using the Infinium MethylationEPIC v2.0 array. Differential methylated analyses were conducted for both EOS-AOS dichotomous comparison and continuous AAO, with stringent adjustment for age, sex, smoking, and estimated cell proportions. At a suggestive significance threshold (p < 5 × 10^-5), we identified 49 differentially methylated positions (DMPs) for EOS-AOS and 126 DMPs for AAO. Genes annotated to the identified DMPs included known schizophrenia and EOS-associated loci (such as ORMDL1, ANXA4, and TRRAP), as well as novel regions linked to cognitive function and neurodevelopment (such as AKAP8L, GPRC5C, and C4orf45). Enrichment analysis implicated key biological processes, including kinase signaling, cell cycle regulation, and microRNA pathways involved in apoptosis and oncogenesis. This study reveals novel differential DNA methylation patterns associated with EOS in the Chinese population and identifies key biological pathways potentially underlying its pathogenesis.