Background Depression is moderately heritable but there is no common genetic variant which has a major effect on susceptibility. It is possible that some very rare variants could have substantial effect sizes and these could be identified from exome sequence data. Methods Data from 50,000 exome-sequenced UK Biobank participants was analysed. Subjects were treated as cases if they had reported having seen a psychiatrist for "nerves, anxiety, tension or depression". Gene-wise weighted burden analysis was performed to see if there were any genes or sets of genes for which there was an excess of rare, functional variants in cases. Results There were 5,872 cases and 43,862 controls. There were 22,028 informative genes but none produced a statistically significant result after correction for multiple testing. Of the 25 genes individually significant at p<0.001 none appeared to be a biologically plausible candidate. No set of genes achieved statistical significance after correction for multiple testing and those with the lowest p values again did not appear to be biologically plausible candidates. Limitations The phenotype is based on self-report and the cases are likely to somewhat heterogeneous. The number of cases is on the low side for a study of exome sequence data. Conclusions The results conform exactly with the expectation under the null hypothesis. It seems unlikely that depression genetics research will produce findings that might have a substantial clinical impact until far larger samples become available.

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