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, Sinéad Chapman, 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
Pages (from-to)5239-5250
Number of pages12
JournalMolecular Psychiatry
Volume26
Issue number9
Early online date22 Jan 2021
DOIs
Publication statusPublished - Sept 2021

Bibliographical note

Funding Information:
Acknowledgements Funding for this study is from: International Bipolar Sequencing Consortium (NIMH R01 MH 110437) (P.Z. M.B., J.P., N.F., P.S.); Whole Genome Sequencing for Schizophrenia and Biopolar Disorder in the GPS (NIMH UO1 MH105653) (M.B, R.M. M.); Whole Genome and Exome Sequencing for Bipolar Disorder (NIMH R01 MH 094145) (M.B.); Multi-ethnic GWAS of Bipolar I Disorder (NIH R01 MH 085543) (C.S.); Genetic Epidemiology Research in Adult Health and Aging (GERA RC2 AG036607) (C.S., N.R.) from the Kaiser Permanente Research Program on Genes, Environment, and Health; Rare Bipolar Loci Identification Through Synaptome Sequencing (NIMH R01 MH 087979 and MH 087992) (J.P., W.R.M); 2/2 Large Scale Genetic Studies of Schizophrenia in Sweden (R01MH095034) (E.A.S.); 1/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder (R01MH106531) (E.A.S.); 1/2 Large Scale Genetic Studies of Schizophrenia in Sweden (R01MH077139) (P.F.S.); 2/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder (R01MH106527) (S.A.M.); The Dalio Foundation (B.N.).

Funding Information:
Conflict of interest XJ had no conflicts during the time he contributed to this study, and declares he is now an employee at Genentech. AEL and EAS had no conflicts during the time they contributed to this study, and declare they are now employees at Regeneron. ML declares that, over the past 36 months, he has received lecture honoraria from Lundbeck pharmaceutical. CL is a member of the Myriad Neuroscience R&D SAB. BN is a Deep Genomics-Member, Scientific Advisory Board; Camp4 Therapeutics Corporation-Consultant, Scientific Advisory Board; Takeda Pharmaceutical-Consultant; Biogen-Consultant, Genomics Analytics Advisory Panel. MO has a research grant from Takeda Pharmaceuticals. JS is an unpaid member of the Bipolar/ Depression Research Community Advisory Panel of 23andMe.

Publisher Copyright:
© 2021, The Author(s).

Funding

Acknowledgements Funding for this study is from: International Bipolar Sequencing Consortium (NIMH R01 MH 110437) (P.Z. M.B., J.P., N.F., P.S.); Whole Genome Sequencing for Schizophrenia and Biopolar Disorder in the GPS (NIMH UO1 MH105653) (M.B, R.M. M.); Whole Genome and Exome Sequencing for Bipolar Disorder (NIMH R01 MH 094145) (M.B.); Multi-ethnic GWAS of Bipolar I Disorder (NIH R01 MH 085543) (C.S.); Genetic Epidemiology Research in Adult Health and Aging (GERA RC2 AG036607) (C.S., N.R.) from the Kaiser Permanente Research Program on Genes, Environment, and Health; Rare Bipolar Loci Identification Through Synaptome Sequencing (NIMH R01 MH 087979 and MH 087992) (J.P., W.R.M); 2/2 Large Scale Genetic Studies of Schizophrenia in Sweden (R01MH095034) (E.A.S.); 1/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder (R01MH106531) (E.A.S.); 1/2 Large Scale Genetic Studies of Schizophrenia in Sweden (R01MH077139) (P.F.S.); 2/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder (R01MH106527) (S.A.M.); The Dalio Foundation (B.N.). Conflict of interest XJ had no conflicts during the time he contributed to this study, and declares he is now an employee at Genentech. AEL and EAS had no conflicts during the time they contributed to this study, and declare they are now employees at Regeneron. ML declares that, over the past 36 months, he has received lecture honoraria from Lundbeck pharmaceutical. CL is a member of the Myriad Neuroscience R&D SAB. BN is a Deep Genomics-Member, Scientific Advisory Board; Camp4 Therapeutics Corporation-Consultant, Scientific Advisory Board; Takeda Pharmaceutical-Consultant; Biogen-Consultant, Genomics Analytics Advisory Panel. MO has a research grant from Takeda Pharmaceuticals. JS is an unpaid member of the Bipolar/ Depression Research Community Advisory Panel of 23andMe.

FundersFunder number
International Bipolar Sequencing Consortium
Rare Bipolar Loci Identification Through Synaptome SequencingR01 MH 087979, MH 087992
National Institutes of Health
National Institute of Mental HealthR01MH077139, R01 MH 110437, R01MH087992, R01MH106527, R01MH087979, R01 MH 085543, R01MH095034, R01MH106531, U01MH105653, R01 MH 094145
National Institute on AgingGERA RC2 AG036607
Robert Wood Johnson Foundation
Wayne and Gladys Valley Foundation
Takeda Pharmaceuticals North America
Dalio Foundation
Kaiser Permanente Washington Health Research Institute

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