Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia.
Duncan S PalmerDaniel P HowriganSinéad B ChapmanRolf AdolfssonNick BassDouglas H R BlackwoodMarco P M BoksChia-Yen ChenClaire ChurchhouseAiden P CorvinNicholas CraddockDavid CurtisArianna Di FlorioFaith DickersonNelson A FreimerFernando S GoesXiaoming JiaIan R JonesLisa A JonesLina JonssonRene S KahnMikaél LandénAdam E LockeAndrew M McIntoshAndrew McQuillinDerek W MorrisMichael C O'DonovanRoel A OphoffMichael J OwenNancy L PedersenDanielle PosthumaAndreas ReifNeil RischCatherine SchaeferLaura J ScottTarjinder SinghJordan W SmollerMatthew SolomonsonDavid St ClairEli A StahlAnnabel VreekerJames T R WaltersWeiqing WangNicholas A WattsRobert YolkenPeter P ZandiBenjamin M NealePublished in: Nature genetics (2022)
We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10 -9 ). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.
Keyphrases
- bipolar disorder
- genome wide
- copy number
- genome wide identification
- major depressive disorder
- dna methylation
- systematic review
- high resolution
- genome wide analysis
- binding protein
- risk factors
- genome wide association
- signaling pathway
- amino acid
- gene expression
- randomized controlled trial
- protein protein
- radiation therapy
- meta analyses
- cell proliferation