Wellbeing, a key aspect of mental health, is moderately heritable with varying estimates reported from independent studies employing a variety of instruments. Recent genome‐wide association studies (GWAS) have enabled the construction of polygenic scores (PGS) for wellbeing, providing the opportunity for direct comparisons of the variance explained by PGS for different instruments commonly employed in the field. Nine wellbeing measurements (multi‐item and single‐item), two personality domains (NEO‐FFI neuroticism and extraversion), plus the depression domain of the DASS‐42 were drawn from a larger self‐report battery applied to the TWIN‐E study—an Australian longitudinal twin cohort (N = 1660). Heritability was estimated using univariate twin modeling and 12‐month test–retest reliability was estimated using intra‐class correlation. PGS were constructed using wellbeing GWAS summary‐statistics from Baselmans et al. (Nat Genet. 2019), and the variance explained estimated using linear models. Last, a GWAS was performed using COMPAS‐W, a quantitative composite wellbeing measure, to explore its utility in genomic studies. Heritability estimates ranged from 23% to 47% across instruments, and multi‐item measures showed higher heritability and test–retest reliability than single‐item measures. The variance explained by PGS was ~0.5% to 1.5%, with considerable variation between measures, and within each measure over 12 months. Five loci with suggestive association (p < 1 × 10−5) were identified from this initial COMPAS‐W wellbeing GWAS. This work highlights the variability across measures currently employed in wellbeing research, with multi‐item and composite measures favored over single‐item measures. While wellbeing PGS are useful in a research setting, they explain little of the phenotypic variance, highlighting gaps for improved gene discovery.

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Background Although mental wellbeing has been linked with positive health outcomes, including longevity and improved emotional and cognitive functioning, studies examining the underlying neural mechanisms of both subjective and psychological wellbeing have been sparse. We assessed whether both forms of wellbeing are associated with neural activity engaged during positive and negative emotion processing and the extent to which this association is driven by genetics or environment. Methods We assessed mental wellbeing in 230 healthy adult monozygotic and dizygotic twins using a previously validated questionnaire (COMPAS-W) and undertook functional magnetic resonance imaging during a facial emotion viewing task. We used linear mixed models to analyse the association between COMPAS-W scores and emotion-elicited neural activation. Univariate twin modelling was used to evaluate heritability of each brain region. Multivariate twin modelling was used to compare twin pairs to assess the contributions of genetic and environmental factors to this association. Results Higher levels of wellbeing were associated with greater neural activity in the dorsolateral prefrontal cortex, localised in the right inferior frontal gyrus (IFG), in response to positive emotional expressions of happiness. Univariate twin modelling showed activity in the IFG to have 20% heritability. Multivariate twin modelling suggested that the association between wellbeing and positive emotion-elicited neural activity was driven by common variance from unique environment (r = 0.208) rather than shared genetics. Conclusions Higher mental wellbeing may have a basis in greater engagement of prefrontal neural regions in response to positive emotion, and this association may be modifiable by unique life experiences.