Epigenome-Wide Analysis of DNA Methylation and Optimism in Women and Men

Cuicui Wang*, Dawn L. DeMeo, Eric S. Kim, Andres Cardenas, Kelvin C. Fong, Lewina O. Lee, Avron Spiro, Eric A. Whitsel, Steve Horvath, Lifang Hou, Andrea A. Baccarelli, Yun Li, James D. Stewart, Jo Ann E. Manson, Francine Grodstein, Laura D. Kubzansky, Joel D. Schwartz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Objective: Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized that DNAm would differ among older individuals who are more versus less optimistic. Methods: Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities (n = 3816) and men (only White, n = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the individual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the “number of independent degrees of freedom” approach: effective degrees of freedom correction using the number of principal components (PCs), explaining >95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathway analyses using the Ingenuity Pathway Analysis software. Results: We found that essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm-optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, and neurodevelopmental and neurodegenerative disorders. Conclusion: Our findings provide new insights into possible mechanisms underlying optimism and health.

Original languageEnglish (US)
Pages (from-to)89-97
Number of pages9
JournalPsychosomatic medicine
Issue number1
StatePublished - Jan 1 2023


  • DNA methylation
  • epigenome-wide association study
  • mechanism
  • optimism

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Applied Psychology


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