Genome-wide association study of positive and negative affect reveals shared genetic architecture and a potential...

Altered affect and cognitive dysfunction are burdensome features of many neuropsychiatric conditions that are highly comorbid, remain poorly understood, and have few efficacious treatments. Exploring their genetic architecture and causal relationships may provide insight into their aetiology and comorbidity. Compared to related but distinct traits (depression, wellbeing, neuroticism), findings from genome-wide association studies (GWAS) of positive and negative affect may be informative due to these phenotypes being less heterogenous (compared to broader phenotypes of wellbeing and depression), whilst still retaining important clinical relevance as potential targets for indirect intervention (compared to neuroticism which may be less modifiable). Using data from the Lifelines Cohort Study, we conducted the first GWAS of positive and negative affect using a validated measure (N = 57,946), and four cognitive domains: working memory, reaction time, learning and memory, and executive function (N ≥ 35,729). We then assessed genetic overlap and potential causal relationships using genetic correlation and bidirectional Mendelian randomization (MR) analyses, incorporating large GWAS on related-albeit distinct-phenotypes (depression, anxiety, wellbeing, general cognitive ability [GCA]). We identified one SNP that reached genome-wide significance (p < 5 × 10^-8) for reaction time, and many independent SNPs with suggestive associations for other phenotypes (N = 11-20). For most phenotypes, exploratory gene mapping indicated that SNPs with suggestive associations have higher gene expression in brain tissue compared to other tissues; however, this only met Bonferroni-corrected p-value threshold criteria for positive affect and visual learning and memory. Genetic correlations between negative and positive affect suggest that they are dissociable constructs (r_g = - 0.18). GCA has higher genetic overlap with negative affect than with positive affect (r_g = - 0.19 vs - 0.06), which could indicate that negative affect and GCA have a higher shared neural basis and/or they exhibit causal relationships. Supporting the latter, MR analyses indicated that higher GCA may reduce negative affect, depression, and anxiety, and increase wellbeing, with little impact on positive affect. Conversely, MR analyses indicated that higher risk of depression and lower wellbeing may causally reduce GCA. Together, these findings suggest that interventions that indirectly influence GCA may be valid targets to prevent negative affect, while interventions that indirectly influence depression/wellbeing may be valid targets for GCA.