Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations

Abstract

Although numerous genetic studies have been conducted for bipolar disorder (BD), its genetic architecture remains elusive. Here we perform, to the best of our knowledge, the first trio-based exome sequencing study for BD to investigate potential roles of de novo mutations in the disease etiology. We identified 71 de novo point mutations and one de novo copy-number mutation in 79 BD probands. Among the genes hit by de novo loss-of-function (LOF; nonsense, splice site or frameshift) or protein-altering (LOF, missense and inframe indel) mutations, we found significant enrichment of genes highly intolerant (first percentile of intolerant genes assessed by Residual Variation Intolerance Score) to protein-altering variants in general population, an observation that is also reported in autism and schizophrenia. When we performed a joint analysis using the data of schizoaffective disorder in published studies, we found global enrichment of de novo LOF and protein-altering mutations in the combined group of bipolar I and schizoaffective disorders. Considering relationship between de novo mutations and clinical phenotypes, we observed significantly earlier disease onset among the BD probands with de novo protein-altering mutations when compared with non-carriers. Gene ontology enrichment analysis of genes hit by de novo protein-altering mutations in bipolar I and schizoaffective disorders did not identify any significant enrichment. These results of exploratory analyses collectively point to the roles of de novo LOF and protein-altering mutations in the etiology of bipolar disorder and warrant further large-scale studies.

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

“…Rate of de novo mutations was higher in bipolar I and schizoaffective disorders than controls, and they were enriched for calcium binding proteins. These findings collectively suggested the role of de novo mutations in BD …”

Schizophrenia and the neurodevelopmental continuum:evidence from genomics

“…Bipolar disorder has been much less extensively studied by exome sequencing. Consistent with the picture that is more clearly emerging from studies of intellectual disability, autism spectrum disorders and schizophrenia, one small study found an excess of de novo loss of function and protein altering variants in mutation intolerant genes, and an association with early onset, while a second study found that damaging variants were enriched for genes previously found to contain de novo mutations in autism and schizophrenia.…”

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

“…An enrichment of rare, moderate to highly penetrant copy number variants (CNVs) and de novo CNVs are seen in SCZ patients(CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, 2017; Gulsuner and McClellan, 2015; Kirov et al, 2012; Stone et al, 2008; Szatkiewicz et al, 2014), while, the involvement of CNVs in BD is less clear(Green et al, 2016). Although the role of de novo single nucleotide variants in BD and SCZ has been investigated in only a handful of studies, enrichment in pathways associated with the postsynaptic density has been reported for SCZ, but not BD(Fromer et al, 2014; Kataoka et al, 2016). Identifying disorder-specific variants and quantifying the contribution of genetic variation to specific symptom dimensions remain important open questions.…”