Logo image
Back
Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder
Journal article   Open access   Peer reviewed

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Xiaoming Jia, Fernando S. Goes, Adam E. Locke, Duncan Palmer, Weiqing Wang, Sarah Cohen-Woods, Giulio Genovese, Anne U. Jackson, Chen Jiang, Mark Kvale, …
Molecular psychiatry, Vol.26(9), pp.5239-5250
09/01/2021
DOI: 10.1038/s41380-020-01006-9
PMID: 33483695
url
https://doi.org/10.1038/s41380-020-01006-9View
Published (Version of record) Open Access

Related content

Was corrected by

Abstract

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 x 10(-4)), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
 Psychiatry Biochemistry & Molecular Biology Life Sciences & Biomedicine Neurosciences Neurosciences & Neurology Science & Technology

Details

Metrics

20 Record Views
15 Times Cited - Web of Science
Logo image