Meta-Analysis

. 2021 Sep;26(9):5239-5250.

doi: 10.1038/s41380-020-01006-9. Epub 2021 Jan 22.

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Xiaoming Jia^#¹, Fernando S Goes^#², Adam E Locke^#³, Duncan Palmer^#⁴, Weiqing Wang^#⁵, Sarah Cohen-Woods^{6

7}, Giulio Genovese⁴, Anne U Jackson⁸, Chen Jiang⁹, Mark Kvale¹⁰, Niamh Mullins¹¹, Hoang Nguyen⁵, Mehdi Pirooznia¹², Margarita Rivera^{7

13}, Douglas M Ruderfer¹⁴, Ling Shen⁹, Khanh Thai⁹, Matthew Zawistowski⁸, Yongwen Zhuang⁸, Gonçalo Abecasis⁸, Huda Akil¹⁵, Sarah Bergen¹⁶, Margit Burmeister^{15

17

18

19}, Sinéad Chapman⁴, Melissa DelaBastide²⁰, Anders Juréus¹⁶, Hyun Min Kang⁸, Pui-Yan Kwok¹⁰, Jun Z Li^{17

18}, Shawn E Levy²¹, Eric T Monson²², Jennifer Moran²³, Janet Sobell²⁴, Stanley Watson¹⁵, Virginia Willour²², Sebastian Zöllner^{8

19}, Rolf Adolfsson²⁵, Douglas Blackwood²⁶, Michael Boehnke⁸, Gerome Breen^{7

27}, Aiden Corvin²⁸, Nick Craddock²⁹, Arianna DiFlorio²⁹, Christina M Hultman¹⁶, Mikael Landen^{16

30}, Cathryn Lewis^{7

31}, Steven A McCarroll³², W Richard McCombie²⁰, Peter McGuffin⁷, Andrew McIntosh^{26

33}, Andrew McQuillin³⁴, Derek Morris^{28

35}, Richard M Myers²¹, Michael O'Donovan²⁹, Roel Ophoff^{36

37}, Marco Boks³⁷, Rene Kahn³⁸, Willem Ouwehand³⁹, Michael Owen²⁹, Carlos Pato^{24

40}, Michele Pato^{24

41}, Danielle Posthuma^{42

43}, James B Potash², Andreas Reif⁴⁴, Pamela Sklar⁵, Jordan Smoller^{4

45}, Patrick F Sullivan⁴⁶, John Vincent^{47

48}, James Walters²⁹, Benjamin Neale^{4

49}, Shaun Purcell^{50

51}, Neil Risch¹⁰, Catherine Schaefer⁹, Eli A Stahl⁵, Peter P Zandi⁵², Laura J Scott⁵³

Affiliations

¹ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94158, USA.
² Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA.
³ Division of Genomics & Bioinformatics, Department of Medicine and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63108, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁵ Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁶ Discipline of Psychology and Flinders Centre for Innovation in Cancer, Flinders University, Adelaide, SA, Australia.
⁷ Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁸ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
⁹ Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94611, USA.
¹⁰ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA.
¹¹ Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
¹² Bioinformatics and Computational Core, National Heart, Lung, and Blood Institute, Bethesda, MD, 20892, USA.
¹³ Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain.
¹⁴ Departments of Medicine, Psychiatry, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
¹⁵ Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁷ Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁸ Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁹ Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109, USA.
²⁰ Division of Research, Cold Spring Harbor Laboratory, Cold Spring, Harbor, NY, 11797, USA.
²¹ HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
²² Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
²³ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, 02114, USA.
²⁴ Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, 90033, USA.
²⁵ Departments of Clinical Sciences and Psychiatry, Umea University, Umea, Sweden.
²⁶ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
²⁷ NIHR BRC for Mental Health, King's College London, London, UK.
²⁸ Department of Psychiatry and Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
²⁹ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.
³⁰ Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
³¹ Department of Medical & Molecular Genetics, King's College London, London, UK.
³² Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
³³ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
³⁴ Division of Psychiatry, University College London, London, UK.
³⁵ Discipline of Biochemistry, Neuroimaging and Cognitive Genomics (NICOG) Centre, National University of Ireland Galway, Galway, Ireland.
³⁶ Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA, 90095, USA.
³⁷ Department of Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, the Netherlands.
³⁸ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
³⁹ Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
⁴⁰ SUNY Downstate Medical Center, Brooklyn, NY, 11203, USA.
⁴¹ Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, NY, 11203, USA.
⁴² Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁴³ Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
⁴⁴ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
⁴⁵ Department of Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁴⁶ Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
⁴⁷ Molecular Neuropsychiatry and Development Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction & Mental Health, Toronto, ON, Canada.
⁴⁸ Department of Psychiatry and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
⁴⁹ Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁵⁰ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
⁵¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁵² Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. pzandi1@jhmi.edu.
⁵³ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA. ljst@umich.edu.

^# Contributed equally.

PMID: 33483695
PMCID: PMC8295400
DOI: 10.1038/s41380-020-01006-9

Meta-Analysis

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Xiaoming Jia et al. Mol Psychiatry. 2021 Sep.

. 2021 Sep;26(9):5239-5250.

doi: 10.1038/s41380-020-01006-9. Epub 2021 Jan 22.

Authors

Affiliations

¹ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94158, USA.
² Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA.
³ Division of Genomics & Bioinformatics, Department of Medicine and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63108, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁵ Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁶ Discipline of Psychology and Flinders Centre for Innovation in Cancer, Flinders University, Adelaide, SA, Australia.
⁷ Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁸ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
⁹ Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94611, USA.
¹⁰ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA.
¹¹ Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
¹² Bioinformatics and Computational Core, National Heart, Lung, and Blood Institute, Bethesda, MD, 20892, USA.
¹³ Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain.
¹⁴ Departments of Medicine, Psychiatry, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
¹⁵ Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁷ Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁸ Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁹ Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109, USA.
²⁰ Division of Research, Cold Spring Harbor Laboratory, Cold Spring, Harbor, NY, 11797, USA.
²¹ HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
²² Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
²³ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, 02114, USA.
²⁴ Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, 90033, USA.
²⁵ Departments of Clinical Sciences and Psychiatry, Umea University, Umea, Sweden.
²⁶ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
²⁷ NIHR BRC for Mental Health, King's College London, London, UK.
²⁸ Department of Psychiatry and Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
²⁹ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.
³⁰ Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
³¹ Department of Medical & Molecular Genetics, King's College London, London, UK.
³² Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
³³ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
³⁴ Division of Psychiatry, University College London, London, UK.
³⁵ Discipline of Biochemistry, Neuroimaging and Cognitive Genomics (NICOG) Centre, National University of Ireland Galway, Galway, Ireland.
³⁶ Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA, 90095, USA.
³⁷ Department of Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, the Netherlands.
³⁸ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
³⁹ Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
⁴⁰ SUNY Downstate Medical Center, Brooklyn, NY, 11203, USA.
⁴¹ Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, NY, 11203, USA.
⁴² Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁴³ Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
⁴⁴ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
⁴⁵ Department of Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁴⁶ Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
⁴⁷ Molecular Neuropsychiatry and Development Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction & Mental Health, Toronto, ON, Canada.
⁴⁸ Department of Psychiatry and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
⁴⁹ Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁵⁰ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
⁵¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁵² Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. pzandi1@jhmi.edu.
⁵³ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA. ljst@umich.edu.

^# Contributed equally.

PMID: 33483695
PMCID: PMC8295400
DOI: 10.1038/s41380-020-01006-9

Erratum in

Correction: Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.
Jia X, Goes FS, Locke AE, Palmer D, Wang W, Cohen-Woods S, Genovese G, Jackson AU, Jiang C, Kvale M, Mullins N, Nguyen H, Pirooznia M, Rivera M, Ruderfer DM, Shen L, Thai K, Zawistowski M, Zhuang Y, Abecasis G, Akil H, Bergen S, Burmeister M, Chapman S, DelaBastide M, Juréus A, Kang HM, Kwok PY, Li JZ, Levy SE, Monson ET, Moran J, Sobell J, Watson S, Willour V, Zöllner S, Adolfsson R, Blackwood D, Boehnke M, Breen G, Corvin A, Craddock N, DiFlorio A, Hultman CM, Landen M, Lewis C, McCarroll SA, Richard McCombie W, McGuffin P, McIntosh A, McQuillin A, Morris D, Myers RM, O'Donovan M, Ophoff R, Boks M, Kahn R, Ouwehand W, Owen M, Pato C, Pato M, Posthuma D, Potash JB, Reif A, Sklar P, Smoller J, Sullivan PF, Vincent J, Walters J, Neale B, Purcell S, Risch N, Schaefer C, Stahl EA, Zandi PP, Scott LJ. Jia X, et al. Mol Psychiatry. 2021 Sep;26(9):5251. doi: 10.1038/s41380-021-01063-8. Mol Psychiatry. 2021. PMID: 33674754 Free PMC article. No abstract available.

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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**Fig. 1. P-LP variant distribution.**
Minor allele counts for variants classified as P or LP from 9,309 individuals in the BSC cohort show that 81% of P-LP variants are singleton mutations. 38% of P-LP variants are not present in gnomAD. 44% of such variants are classified as P (predominantly splice site and nonsense variants), and 56% are classified as LP (predominantly missense variants). P pathogenic, LP likely pathogenic, S Splice site, N nonsense, M missense, ACMG American College of Medical Genetics, GnomAD Genome Aggregation Database.

**Fig. 2. P-LP variant burden in candidate BD- and SCZ-related gene sets.**
Meta-analysis of Firth logistic regression of P-LP variants shows that BD cases in BSC cohorts appear to carry a higher burden of P-LP alleles in three BD GWAS-derived gene sets. Horizontal bars represent 95% confidence intervals. No enrichment of P-LP variants was observed in three schizophrenia GWAS-derived gene sets, in two neuron synaptic-related genesets (RBFOX2- and FMRP-related genes), in genes classified as LOF-intolerant, or in all genes across the exome. P values are one-sided for enrichment of P-PL variants in BD cases and derived from the meta-analysis Z-score. Numbers in parentheses represent the number of genes with P-LP variants and total number of genes within each gene set, respectively. BD bipolar disorder, OR odds ratio, P-LP pathogenic or likely pathogenic, GWAS genome-wide association study, LOF loss-of-function.

**Fig. 3. P-LP variant burden in BD GWAS gene sets within BSC discovery and BipEx replication cohorts.**
Forest plots of log odds ratios (Firth logistic regressions) for association between P-LP variant burden and BD across seven cohorts/ethnicities in the BSC study (top) and across six strata in the BipEx replication cohort (bottom). p values are one-sided for enrichment of P-PL variants in BD cases and derived from the meta-analysis Z-score. Meta-analysis shows that individuals with BD do not carry a replicable enrichment of P-LP variants in 165 BD GWAS-derived genes, in 153 BD genes identified using MAGMA, or in 81 genes that overlap between the BD GWAS and BD MAGMA gene sets. Horizontal black lines indicate 95% confidence intervals around the effect size. Unshaded boxes indicate absence of P-LP variants within a specific cohort. Gray boxes indicate meta-analysis within the BSC (discovery) and BipEx (replication) cohorts, respectively, and black box indicates meta-analysis across all BSC and BipEx cohorts. Numbers in parentheses indicate the number of BD cases and controls. BSC Bipolar Sequencing Consortium, BipEx Bipolar Exomes collection, REP replication cohorts, META meta-analysis.

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References

1. Ferrari AJ, Stockings E, Khoo JP, Erskine HE, Degenhardt L, Vos T, et al. The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar Disord. 2016;18:440–50. - PubMed
1. Merikangas KR, Jin R, He J-P, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68:241–51. - PMC - PubMed
1. Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016;387:1561–72. - PubMed
1. Beasley CL, Honer WG, von Bergmann K, Falkai P, Lütjohann D, Bayer TA. Reductions in cholesterol and synaptic markers in association cortex in mood disorders. Bipolar Disord. 2005;7:449–55. - PubMed
1. Martinowich K, Schloesser RJ, Manji HK. Bipolar disorder: from genes to behavior pathways. J Clin Investig. 2009;119:726–36. - PMC - PubMed

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Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Affiliations

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials