@misc{10481/66733,
year = {2021},
month = {1},
url = {http://hdl.handle.net/10481/66733},
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 × 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.},
organization = {International Bipolar Sequencing Consortium (NIMH) 

R01 MH 110437},
organization = {Whole Genome Sequencing for Schizophrenia and Biopolar Disorder in the GPS (NIMH) 

UO1 MH105653},
organization = {Whole Genome and Exome Sequencing for Bipolar Disorder (NIMH) 

R01 MH 094145},
organization = {Multi-ethnic GWAS of Bipolar I Disorder (NIH) 

R01 MH 085543},
organization = {Genetic Epidemiology Research in Adult Health and Aging (GERA) 

RC2 AG036607},
organization = {Kaiser Permanente Research Program on Genes, Environment, and Health},
organization = {Rare Bipolar Loci Identification Through Synaptome Sequencing (NIMH) 

R01 MH 087979
MH 087992},
organization = {2/2 Large Scale Genetic Studies of Schizophrenia in Sweden 

R01MH095034},
organization = {1/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder 

R01MH106531},
organization = {1/2 Large Scale Genetic Studies of Schizophrenia in Sweden 

R01MH077139},
organization = {2/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder 

R01MH106527},
organization = {Dalio Foundation},
publisher = {Springer Nature},
title = {Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder},
doi = {10.1038/s41380-020-01006-9},
author = {Jia, Xiaoming and Rivera Sánchez, Margarita},
}