Abstract
Altered affect and cognitive dysfunction are transdiagnostic, burdensome, and pervasive features of many psychiatric conditions which remain poorly understood and have few efficacious treatments. Research on the genetic architecture of these phenotypes and causal relationships between them may provide insight into their aetiology and comorbidity. Using data from the Lifelines Cohort Study, we conducted genome-wide association studies (GWAS) on positive and negative affect and four cognitive domains (working memory, reaction time, visual learning and memory, executive function). Using publicly available large GWAS on related - albeit distinct-phenotypes (depression, anxiety, wellbeing, general cognitive ability [GCA]) we conducted genetic correlation and Mendelian randomization (MR) analyses to examine genetic overlap and causal relationships. We identified one genome-wide hit (p<5×10(-8)) for reaction time, and many loci with suggestive associations (p<5×10(-6); N range= 11-20 independent hits) for other phenotypes. For most phenotypes, gene mapping and tissue expression analysis of suggestive hits from the GWAS showed increased gene expression in brain tissue compared to other tissues. As predicted, negative affect is genetically correlated with mental health phenotypes (depression r (g)=0.51; anxiety r (g)=0.70; wellbeing r (g) = -0.71) and cognitive domains are genetically correlated with GCA and brain volume (r (g) ≤ 0.66). Genetic correlations between negative and positive affect suggest that they are dissociable constructs (r (g) = -0.18) with negative affect having higher genetic overlap with GCA than positive affect (r (g) =-0.19 vs -0.06). This could indicate that negative affect has a higher shared neural basis with GCA than positive affect and/or GCA and negative affect may exhibit causal relationships. MR analyses suggest potential causal effects of higher GCA on reduced negative affect, reduced risk of depression and anxiety, and higher wellbeing, but little impact on positive affect. We also report evidence for potential causal effects of depression and lower wellbeing on reduced GCA. Taken together, these results suggests that GCA may be a valid target for negative affect (but not positive affect) and depression and wellbeing may be valid targets for GCA.