Sex effects on DNA methylation affect discovery in epigenome-wide association study of schizophrenia

• Published in: Molecular psychiatry 2024-08, Vol.29 (8), p.2467-2477
• Main Authors: Tesfaye, Markos, Spindola, Leticia M., Stavrum, Anne-Kristin, Shadrin, Alexey, Melle, Ingrid, Andreassen, Ole A., Le Hellard, Stephanie
• Format: Article
• Language: English
• Subjects: 45/43; 631/1647; 631/208; Adult; Behavioral Sciences; Biological Psychology; Case-Control Studies; CpG Islands - genetics; DNA methylation; DNA Methylation - genetics; Epidemiology; Epigenesis, Genetic - genetics; Epigenetics; Epigenome - genetics; Epigenomics - methods; Female; Females; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study - methods; Humans; Male; Males; Medicine; Medicine & Public Health; Mental disorders; Meta-analysis; Middle Aged; Molecular modelling; Neurosciences; Peripheral blood; Pharmacotherapy; Psychiatry; Schizophrenia; Schizophrenia - genetics; Sex Characteristics; Sex differences; Sex Factors
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-024-02513-9

Sex differences in the epidemiology and clinical characteristics of schizophrenia are well-known; however, the molecular mechanisms underlying these differences remain unclear. Further, the potential advantages of sex-stratified meta-analyses of epigenome-wide association studies (EWAS) of schizophrenia have not been investigated. Here, we performed sex-stratified EWAS meta-analyses to investigate whether sex stratification improves discovery, and to identify differentially methylated regions (DMRs) in schizophrenia. Peripheral blood-derived DNA methylation data from 1519 cases of schizophrenia (male n  = 989, female n  = 530) and 1723 controls (male n  = 997, female n  = 726) from three publicly available datasets, and the TOP cohort were meta-analyzed to compare sex-specific, sex-stratified, and sex-adjusted EWAS. The predictive power of each model was assessed by polymethylation score (PMS). The number of schizophrenia-associated differentially methylated positions identified was higher for the sex-stratified model than for the sex-adjusted one. We identified 20 schizophrenia-associated DMRs in the sex-stratified analysis. PMS from sex-stratified analysis outperformed that from sex-adjusted analysis in predicting schizophrenia. Notably, PMSs from the sex-stratified and female-only analyses, but not those from sex-adjusted or the male-only analyses, significantly predicted schizophrenia in males. The findings suggest that sex-stratified EWAS meta-analyses improve the identification of schizophrenia-associated epigenetic changes and highlight an interaction between sex and schizophrenia status on DNA methylation. Sex-specific DNA methylation may have potential implications for precision psychiatry and the development of stratified treatments for schizophrenia.