Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia

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 × 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.

Regulome-wide association study identifies enhancer properties associated with risk for schizophrenia

“…Enhancers that contact genes with a given ontology term were assigned to the enhancer set for that term, and the resultant enhancer sets were tested for association with risk using MAGMA’s gene set mode. The gene sets are available in Supplementary Table 1 and are derived from the following datasets: genes intolerant of loss-of-function variants from gnomAD (pLI >= 0.9 or LOEUF deciles 1 or 2) [50]; risk genes from studies of rare variants in four disorders, including severe developmental disorder risk genes from the Deciphering Developmental Disorders consortium’s DDG2P database (Disorders of Brain Development) [51], autism spectrum disorder risk genes from the Autism Sequencing Consortium (Autism risk [exomes]) [52], bipolar disorder risk genes from the BipEx Consortium [53]; genes identified from large-scale GWAS, identified by gene-based analyses with MAGMA [9] (p < 2.77e-6 unless noted as FDR, in which case adj. p < 0.05) for bipolar disorder [54], major depression [55], and neuroticism [56], differentially expressed genes in the prefrontal cortex of individuals with schizophrenia, bipolar disorder, and autism from the PsychENCODE consortium [57] (http://resource.psychencode.org/Datasets/Derived/DEXgenes_CoExp/DER-13_Disorder_DEX_Genes.csv); genes associated with schizophrenia from SCHEMA [58] (25 genes with SCHEMA P < 0.05; odds ratio = 1.6, P = 0.03); target gene networks of the neuropsychiatric risk genes FMRP, RBFOX1/3, RBFOX2, CHD8, CELF4, and microRNA-137 derived from functional genomics experiments, annotated by Genovese et al [59]; synaptic genes from SynaptomeDB (“GO: Axonal growth cone proteome, GO: Neuron spine”) [60].…”

Using brain cell-type-specific protein interactomes to interpret genetic data in schizophrenia

“…Indeed, two HCN1 interactor genes we identified, HCN4 and AKAP11 , are also enriched for schizophrenia-associated protein-truncating variants (PTVs) in SCHEMA (FDR = 4.2e-3 and 1.3e-2, respectively) ( 15 ). In a recent meta-analysis of schizophrenia and bipolar disorder cases ( 36 ), AKAP11 further emerged as an exome-wide significant ( P = 2.8e-9) gene enriched for ultra-rare PTVs. PTVs are among the most interpretable genetic variants as their effects on disease most commonly track with decreased function and expression of the gene.…”

Whole exome sequencing in the UK Biobank reveals risk geneSLC2A1and biological insights for major depressive disorder

“…Depression GWAS have successfully identified a large number of common-variant risk loci, while the identification of rare coding variants contributing to depression risk has failed to keep pace [1][2][3][4] . Recently, large-scale exome sequencing studies of developmental and other psychiatric disorders have uncovered novel risk genes and shared genetic signals between neuropsychiatric disorders [10][11][12][13][14][15] , suggesting the promise of novel discoveries from exome analysis of depression.…”

“…We tested if damaging rare variant burden were enriched in specific functional gene sets, gene ontology (GO) 26 , the human brain proteome 25 , antidepressant interacted genes 29 , major depressive disorder GWAS risk genes 3 and other neuropsychiatric and neurodevelopmental disease associated genes [10][11][12][13][14]32,33 . We applied logistic regressions by fitting an individual disease status on the number of rare variants in a given gene set the individual carried, controlling for 20 PCs, mean centered age, sex, mean centered age 2 , mean centered age ´ sex and mean centered age 2 ´ sex.…”