Analysis of 200 000 exome-sequenced UK Biobank subjects fails to identify genes influencing probability of developing a mood disorder resulting in psychiatric referral.

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 exome-sequenced subjects failed to implicate any genes or sets of genes in which rare variants were associated with risk of affective disorder requiring specialist treatment. A much larger 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 an obvious biological candidate.

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. This research has been conducted using the UK Biobank Resource.