Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression. Researchers analyzed whole-exome sequencing data from 320,356 UK Biobank participants to identify the impact of rare coding variants on depression risk. They found that rare damaging coding variants in loss-of-function intolerant genes significantly increase depression risk across seven different definitions of depression. The study also showed that the effects of rare variant burden and polygenic risk score on depression risk are additive. Gene set burden analyses revealed overlapping rare genetic variant components with developmental disorder, autism, and schizophrenia. The study provides insights into the contribution of rare coding variants, separately and in conjunction with common variants, on depression with various definitions and their genetic relationships with neurodevelopmental disorders. Depression is a common and heritable psychiatric disorder with high medical and socioeconomic burden. Genome-wide association studies (GWAS) of depression have identified a large number of genetic loci through common variant associations, while the contribution of rare coding variants to depression risk is largely unknown due to the lack of large-scale exome sequenced depression patient samples. Recent large-scale exome sequencing studies have uncovered novel risk genes for neurodevelopmental and psychiatric disorders as well as shared genetic signals between psychiatric disorders, highlighting the importance of further investigating the impact of rare coding variants on depression through large-scale exome sequencing. Depression is known to be clinically heterogeneous and therefore, the case samples included in depression genetic studies often show substantial heterogeneity in their phenotypes. Previous studies have shown that the common variant genetic architecture varies between different depression definitions. In particular, it has been shown that the SNP-based heritability (h_g^2) can vary widely (0.11–0.33) across different depression definitions in the UK Biobank (UKB), and the genetic correlation (r_g) estimates can deviate from one between some of these depression definitions. It is critical to consider this heterogeneity when investigating the impact of rare coding variants on depression. The recently released whole-exome sequencing data in UKB made it possible to investigate the impact of rare coding variants on depression in the context of its heterogeneity. Here, we analyzed exome sequencing, survey, questionnaire, and electronic health record (EHR) data from 454,787 participants in UKB. As the common variant genetic architecture changes with depression definitions in UKB, we followed the seven previously reported depression definitions with different levels of stringency reported by Cai et al. to identify depression cases and controls in UKB and performed comprehensive genetic analyses on rare coding variants in whole-exome sequencing data across these seven depression phenotypes. The study found that rare damaging coding variants in loss-of-function intolerant genes significantly associate with depression risk. The genetic correlations between depression definitions based on rare PTV and missense variants were strong. The study also showed that the effects of rare variant burden and polygenic risk score on depression risk are additive. The studyWhole-exome sequencing in UK Biobank reveals rare genetic architecture for depression. Researchers analyzed whole-exome sequencing data from 320,356 UK Biobank participants to identify the impact of rare coding variants on depression risk. They found that rare damaging coding variants in loss-of-function intolerant genes significantly increase depression risk across seven different definitions of depression. The study also showed that the effects of rare variant burden and polygenic risk score on depression risk are additive. Gene set burden analyses revealed overlapping rare genetic variant components with developmental disorder, autism, and schizophrenia. The study provides insights into the contribution of rare coding variants, separately and in conjunction with common variants, on depression with various definitions and their genetic relationships with neurodevelopmental disorders. Depression is a common and heritable psychiatric disorder with high medical and socioeconomic burden. Genome-wide association studies (GWAS) of depression have identified a large number of genetic loci through common variant associations, while the contribution of rare coding variants to depression risk is largely unknown due to the lack of large-scale exome sequenced depression patient samples. Recent large-scale exome sequencing studies have uncovered novel risk genes for neurodevelopmental and psychiatric disorders as well as shared genetic signals between psychiatric disorders, highlighting the importance of further investigating the impact of rare coding variants on depression through large-scale exome sequencing. Depression is known to be clinically heterogeneous and therefore, the case samples included in depression genetic studies often show substantial heterogeneity in their phenotypes. Previous studies have shown that the common variant genetic architecture varies between different depression definitions. In particular, it has been shown that the SNP-based heritability (h_g^2) can vary widely (0.11–0.33) across different depression definitions in the UK Biobank (UKB), and the genetic correlation (r_g) estimates can deviate from one between some of these depression definitions. It is critical to consider this heterogeneity when investigating the impact of rare coding variants on depression. The recently released whole-exome sequencing data in UKB made it possible to investigate the impact of rare coding variants on depression in the context of its heterogeneity. Here, we analyzed exome sequencing, survey, questionnaire, and electronic health record (EHR) data from 454,787 participants in UKB. As the common variant genetic architecture changes with depression definitions in UKB, we followed the seven previously reported depression definitions with different levels of stringency reported by Cai et al. to identify depression cases and controls in UKB and performed comprehensive genetic analyses on rare coding variants in whole-exome sequencing data across these seven depression phenotypes. The study found that rare damaging coding variants in loss-of-function intolerant genes significantly associate with depression risk. The genetic correlations between depression definitions based on rare PTV and missense variants were strong. The study also showed that the effects of rare variant burden and polygenic risk score on depression risk are additive. The study