A functional genomic perspective on human well-being

Abstract

To identify molecular mechanisms underlying the prospective health advantages associated with psychological well-being, we analyzed leukocyte basal gene expression profiles in 80 healthy adults who were assessed for hedonic and eudaimonic well-being, as well as potentially confounded negative psychological and behavioral factors. Hedonic and eudaimonic well-being showed similar affective correlates but highly divergent transcriptome profiles. Peripheral blood mononuclear cells from people with high levels of hedonic well-being showed up-regulated expression of a stress-related conserved transcriptional response to adversity (CTRA) involving increased expression of proinflammatory genes and decreased expression of genes involved in antibody synthesis and type I IFN response. In contrast, high levels of eudaimonic well-being were associated with CTRA down-regulation. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity in structuring the observed differences in gene expression associated with eudaimonic well-being (reduced NF-κB and AP-1 signaling and increased IRF and STAT signaling). Transcript origin analysis identified monocytes, plasmacytoid dendritic cells, and B lymphocytes as primary cellular mediators of these dynamics. The finding that hedonic and eudaimonic well-being engage distinct gene regulatory programs despite their similar effects on total well-being and depressive symptoms implies that the human genome may be more sensitive to qualitative variations in well-being than are our conscious affective experiences.

Keywords: gene regulation; social genomics.

Fig. 1.

(A) Relationship between hedonic and eudaimonic well-being (dashed line indicates equivalent levels; n = 80). (B) Tukey mean-difference plot (39) reexpressing individual differences in well-being in terms of total well-being (hedonic plus eudaimonic) and eudaimonic predominance (eudaimonic minus hedonic; dashed line indicates equivalent levels).

Fig. 2.

Expression of the CTRA gene set. (A) Linear model-based estimates of mean difference (±SEM) in expression in a 53-gene CTRA contrast score in PBMCs from individuals with low levels (−2 SD relative to sample mean) vs. high levels (+2 SD) of hedonic well-being and eudaimonic well-being (each adjusting for the other and for demographic and behavioral covariates). (B) Differential expression of CTRA subcomponents: 19 proinflammatory genes, 31 type I IFN response genes, and three antibody synthesis genes.

Fig. 3.

Transcription control pathways and cellular origin. Genes showing ≥1.5-fold differential expression across low levels (−2 SD relative to sample mean) vs. high levels (+2 SD relative to sample mean) of eudaimonic well-being and hedonic well-being were tested for (A) differential activity of specific transcription factors as indicated by TELiS analysis of transcription factor-binding motifs (TFBM) in proximal promoter sequences of up- vs. down-regulated genes (40) and (B) PBMC cell type of origin as indicated by TOA cell-type diagnosticity z-scores (36). (*P < 0.05 after control for multiple hypothesis testing.)