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Importance: Antidepressants are a first line treatment for depression. However, only a third of individuals remit after the first treatment. Genetic variation likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. Objective: Gain insight into underlying biology of antidepressant response, characterize SNP-based heritability and genetic overlap with related outcomes, and evaluate out-of-sample prediction using polygenic scores. Design: Genome-wide meta-analysis of antidepressant response measures, Remission and Percentage Improvement in depression scores. Setting: Multiple international recruitment sites, including clinical trial and open label studies. Participants: Diagnosed with Major Depressive Disorder and assessed for depressive symptoms before and after prescription of an antidepressant medication. Main Outcome(s) and Measure(s): Antidepressant response measured as Remission and Percentage Improvement. Results: Genome-wide analysis of Remission (Nremit=1,852, Nnon-remit=3,299) and Percentage Improvement (N=5,218) identified no genome-wide significant variants. The heritability from common variants was significantly different from zero for Remission (h2=0.132, SE=0.056), but not Percentage Improvement (h2=-0.018, SE=0.032). Polygenic score analysis showed better antidepressant response was associated with lower genetic risk for schizophrenia, and higher genetic propensity for educational attainment. Polygenic scores for antidepressant response demonstrated weak but statistically significant evidence of out-of-sample prediction across cohorts, though results varied in external cohorts. Conclusions and Relevance: This study demonstrates antidepressant response is influenced by common genetic variation, has a genetic overlap with schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

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