Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

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