Genetics of SSRI Antidepressant Use and Relationship to Psychiatric and Medical Traits

Antidepressants are among the most-prescribed drugs worldwide, and selective serotonin reuptake inhibitors (SSRIs) are among the most prescribed antidepressants, most commonly used for major depression. We sought to increase our understanding of the biological relationships between SSRI use and a range of psychiatric traits by conducting Genome Wide Association Study (GWAS) in two large datasets, the UK Biobank (UKB) and the US Million Veteran Program (MVP). We conducted GWAS across 22 autosomes and the X chromosome in 777,952 individuals of European ancestry (191,800 SSRI users, 586,152 controls) and 112,526 individuals of African ancestry (53,499 SSRI users, 59,027 controls). We identified 40 genome-wide significant (GWS) loci, including two on the X chromosome. Using linkage disequilibrium score regression we detected strong correlations between MVP and the independent UKB cohort with use of specific SSRIs (fluoxetine genetic correlation (rg)=0.82 and citalopram rg=0.89) as well as with headaches (rg=0.80), major depressive disorder (MDD; rg=0.77), and spondylosis (rg=0.84), suggesting stability in the trait definition across cohorts. To evaluate differences between the genomic variance captured by the SSRI-use trait vs. MDD, we performed a comparative rg analysis between MDD and the meta-analysis for SSRI exposure and found significant differences, most notably for educational attainment (SSRI rg = -0.38, MDD rg= -0.26), cognitive performance (SSRI rg = -0.31, MDD rg=-0.15), and depression (SSRI rg = 0.80, MDD rg= 0.97). We compared locus discovery for SSRI use and MDD in the MVP, and found greater discovery for SSRI use (28 vs 17 risk loci). SSRI use is likely in part a proxy trait for MDD, while also presenting differences that may prove useful to disentangle MDD from other traits (e.g., anxiety disorders) that use similar pharmacological treatment.