Exome sequencing in bipolar disorder reveals shared risk gene AKAP11 with schizophrenia

Duncan S. Palmer; Daniel P. Howrigan; Sinéad B. Chapman; Rolf Adolfsson; Nicholas James Bass; Douglas Blackwood; Marco P. Boks; Chia‐Yen Chen; Claire L. Churchhouse; Aiden Peter Corvin; Nick J. Craddock; David Curtis; Arianna Di Florio; Faith Dickerson; Fernando S. Goes; Xiaoming Jia; Ian Richard Jones; Lisa Anne Jones; Lina Jönsson; René S. Kahn; Mikael Landén; Adam E. Locke; Andrew Mark McIntosh; Andrew McQuillin; Derek W. Morris; Michael C. O’Donovan; Roel A. Ophoff; Michael John Owen; Nancy L. Pedersen; Daniëlle Posthuma

doi:10.1101/2021.03.09.21252930

Genetic & Genomic MedicinemedRxivMar 9, 2021

Preprint

Exome sequencing in bipolar disorder reveals shared risk gene AKAP11 with schizophrenia

Duncan S. Palmer iD, Daniel P. Howrigan iD, Sinéad B. Chapman iD, Rolf Adolfsson iD, Nicholas James Bass iD, Douglas Blackwood iD, Marco P. Boks iD, Chia‐Yen Chen iD, Claire L. Churchhouse iD, Aiden Peter Corvin iD, Nick J. Craddock iD, David Curtis iD, Arianna Di Florio iD, Faith Dickerson iD, Fernando S. Goes iD, Xiaoming Jia iD, Ian Richard Jones iD, Lisa Anne Jones iD, Lina Jönsson iD, René S. Kahn iD, Mikael Landén iD, Adam E. Locke iD, Andrew Mark McIntosh iD, Andrew McQuillin iD, Derek W. Morris iD, , Benjamin M. Neale iD

Abstract

Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 SCZ cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from GWAS of BD, however, are not significantly enriched for ultra-rare PTVs. Combining BD gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (ultra-rare PTVs seen in 33 cases and 13 controls, OR = 7.06, P = 2.83 x 10-9). At the protein level, AKAP-11 is known to interact with GSK3B, the hypothesized mechanism of action for lithium, one of the few treatments for BD. Overall, our results lend further support to the polygenic basis of BD and demonstrate a role for rare coding variation as a significant risk factor in BD onset.

PDF DOI