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

Cuicui Wang¹, Dawn L DeMeo, Eric S Kim

¹From the Department of Environmental Health (Wang, Fong, Schwartz), Harvard T.H. Chan School of Public Health; Department of Medicine, Brigham and Women's Hospital (DeMeo, Manson), Harvard Medical School; Channing Division of Network Medicine (DeMeo, Grodstein), Brigham and Women's Hospital; Department of Social and Behavioral Sciences (Kim, Kubzansky) and Lee Kum Sheung Center for Health and Happiness (Kim, Kubzansky), Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Psychology (Kim), University of British Columbia, Vancouver, BC, Canada; Division of Environmental Health Sciences (Cardenas), School of Public Health, University of California, Berkeley, Berkeley, California; Department of Population Medicine, Division of Chronic Disease Research Across the Lifecourse (Cardenas), Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts; School of the Environment (Fong), Yale University, New Haven, Connecticut; National Center for Posttraumatic Stress Disorder (Lee), VA Boston Healthcare System; Department Psychiatry (Lee, Spiro), Boston University School of Medicine; Massachusetts Veterans Epidemiology Research and Information Center (Spiro), Veterans Affairs Boston Healthcare System; Department of Epidemiology (Spiro), Boston University School of Public Health, Boston, Massachusetts; Department of Epidemiology (Whitsel), Gillings School of Global Public Health; Department of Medicine (Whitsel), School of Medicine, University of North Carolina, Chapel Hill, North Carolina; Departments of Human Genetics (Horvath) and Biostatistics (Horvath), David Geffen School of Medicine, University of California, Los Angeles, California; Department of Preventive Medicine (Hou), Northwestern Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Environmental Health Sciences (Baccarelli), Columbia Mailman School of Public Health, New York, New York; Departments of Genetics (Li), Biostatistics (Li), and Computer Science (Li), University of North Carolina; Cardiovascular Program, Department of Epidemiology (Stewart), University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina; and Department of Epidemiology (Manson, Grodstein, Schwartz), Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Psychosomatic Medicine

|October 6, 2022

Abstract

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.

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