Abstract Body (Do not enter title and authors here): Background: Associations of anxiety disorder and depression with coronary artery disease (CAD) are heterogeneous between populations. Research questions: How does genetic susceptibility to CAD alter the associations between anxiety and depression and incident CAD? Aims: To investigate how genetic susceptibility to CAD alters the associations of anxiety and depression with incident CAD, comparing and combining anxiety and depression. Methods:This is a prospective cohort study using UK Biobank. Diagnoses of anxiety disorder and depression before the baseline assessment were ascertained through linked hospital admission data. Incident CAD was ascertained through hospital admission and death certificate data after baseline. CAD polygenic risk score (PRS) was obtained from CARDIoGRAMplus4 and categorised into low, intermediate, and high. Cox proportional hazard models were used to examine associations between anxiety and depression and CAD. The product term of PRS and these mental health conditions, and the relative excess risk due to interaction (RERI), were used to investigate the presence of multiplicative and additive interactions, respectively. Results: Our study included 288,152 participants of whom 54.4% were female, with a mean age of 56.4 years. Both anxiety disorder (HR: 2.24, 95% CI: 1.86–2.70) and depression (HR: 2.04, 95% CI: 1.80–2.32) were associated with CAD after adjusting for sociodemographic confounders. There was an addictive interaction between depression and PRS (RERI: 0.86; 95% CI: 0.06–1.65) such that the association between depression and CAD was strongest among those with a high PRS whilst there was no such evidence for anxiety disorder. Anxiety only (HR 1.69, 95% 1.17–2.45), depression only (HR 2.01, 95% CI 1.62–2.49) and concomitant anxiety and depression (HR 3.51, 95% CI 2.26–5.45) were associated with CAD even among people with a low PRS. Lifestyle mediators attenuated all these associations across PRS categories. Conclusions: CAD genetic susceptibility might partly contribute to the clustering of depression and CAD but does not provide a full explanation, nor does it explain the association between anxiety disorder and CAD. Therefore, other mechanisms should be explored.