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, Niamh Mullins, Hoang Nguyen, Mehdi Pirooznia, Margarita Rivera, Douglas M. Ruderfer, Ling Shen, Khanh Thai, Matthew Zawistowski, Yongwen Zhuang, Gonçalo AbecasisHuda Akil, Sarah Bergen, Margit Burmeister, Sinead Champion, Melissa DelaBastide, Anders Juréus, Hyun Min Kang, Pui-Yan Kwok, Jun Z. Li, Shawn E. Levy, Eric T. Monson, Jennifer Moran, Janet Sobell, Stanley Watson, Virginia Willour, Sebastian Zöllner, Rolf Adolfsson, Douglas Blackwood, Michael Boehnke, Gerome Breen, Aiden Corvin, Nick Craddock, Arianna DiFlorio, Christina M. Hultman, Mikael Landen, Cathryn Lewis, Steven A. McCarroll, W. Richard McCombie, Peter McGuffin, Andrew McIntosh, Andrew McQuillin, Derek Morris, Richard M. Myers, Michael O’Donovan, Roel Ophoff, Marco Boks, Rene Kahn, Willem Ouwehand, Michael Owen, Carlos Pato, Michele Pato, Danielle Posthuma, James B. Potash, Andreas Reif, Pamela Sklar, Jordan Smoller, Patrick F. Sullivan, John Vincent, James Walters, Benjamin Neale, Shaun Purcell, Neil Risch, Catherine Schaefer, Eli A. Stahl, Peter P. Zandi*, Laura J. Scott*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
JournalMolecular Psychiatry
Early online date2021
DOIs
Publication statusE-pub ahead of print - 2021

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