Background Depression is moderately heritable but there is no common genetic variant which has a major effect on susceptibility. A previous analysis of 50,000 subjects failed to implicate any genes or sets of genes associated with risk of affective disorder requiring specialist treatment. A large exome-sequenced dataset is now available. Methods Data from 200,632 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 22,886 cases and 176,486 controls. There were 22,642 informative genes but no gene or gene set produced a statistically significant result after correction for multiple testing. None of the genes or gene sets with the lowest p values appeared to be a biologically plausible candidate. Limitations The phenotype is based on self-report and the cases are likely to somewhat heterogeneous. Likewise, it is expected that some of the subjects classed as controls will in fact have suffered from depression or some other psychiatric diagnosis. Conclusions The results conform exactly with the expectation under the null hypothesis. It seems unlikely that the use of common, poorly defined phenotypes will produce useful advances in understanding genetic contributions to affective disorder and it might be preferable to focus instead on obtaining large exome-sequenced samples of conditions such as bipolar 1 disorder and severe, recurrent depression.
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