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Rare variants implicate NMDA receptor signaling and cerebellar gene networks in risk for bipolar disorder

Molecular Psychiatry volume 27, pages 3842–3856 (2022)Cite this article

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Abstract

Bipolar disorder is an often-severe mental health condition characterized by alternation between extreme mood states of mania and depression. Despite strong heritability and the recent identification of 64 common variant risk loci of small effect, pathophysiological mechanisms remain unknown. Here, we analyzed genome sequences from 41 multiply-affected pedigrees and identified variants in 741 genes with nominally significant linkage or association with bipolar disorder. These 741 genes overlapped known risk genes for neurodevelopmental disorders and clustered within gene networks enriched for synaptic and nuclear functions. The top variant in this analysis – prioritized by statistical association, predicted deleteriousness, and network centrality – was a missense variant in the gene encoding D-amino acid oxidase (DAOG131V). Heterologous expression of DAOG131V in human cells resulted in decreased DAO protein abundance and enzymatic activity. In a knock-in mouse model of DAOG131, DaoG130V/+, we similarly found decreased DAO protein abundance in hindbrain regions, as well as enhanced stress susceptibility and blunted behavioral responses to pharmacological inhibition of N-methyl-D-aspartate receptors (NMDARs). RNA sequencing of cerebellar tissue revealed that DaoG130V resulted in decreased expression of two gene networks that are enriched for synaptic functions and for genes expressed, respectively, in Purkinje neurons or granule neurons. These gene networks were also down-regulated in the cerebellum of patients with bipolar disorder compared to healthy controls and were enriched for additional rare variants associated with bipolar disorder risk. These findings implicate dysregulation of NMDAR signaling and of gene expression in cerebellar neurons in bipolar disorder pathophysiology and provide insight into its genetic architecture.

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Fig. 1: Discovery and prioritization of functional rare variants associated with bipolar disorder.
Fig. 2: Effects of DAOG131V on expression and activity of the DAO protein.
Fig. 3: Behavioral characterization of DaoG130V/+ vs. Dao+/+ mice.
Fig. 4: DaoG130V/+ blunts hyperlocomotor response to the NMDAR antagonist MK-801.
Fig. 5: Differentially expressed gene networks in the cerebellum of DaoG130V/+ mice and of humans with bipolar disorder and schizophrenia.

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Data availability

Genome sequences have been deposited in the BIGPOWER database and are available upon request to Dr. Jared Roach (jedroach@uw.edu). RNA-seq data have been deposited in the Neuroscience Multi-Omic Archive (http://data.nemoarchive.org/other/grant/sament/sament/dao_rnaseq/). The DaoG130V/+ mouse line has been made available through the Mutant Mouse Resource and Research Centers (RRID:MMRRC_067164-UCD). All other data are available in the main text or the supplementary materials.

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Acknowledgements

This work was supported by grants from the National Institute of Mental Health (R01 MH094483 to J.R.K.; R01 MH110437 to P.P.Z.; F31 MH123066 to L.M.R.), the National Institute of General Medical Sciences (T32 GM008181 to L.M.R.), the National Institute of General Medical Sciences Center for Systems Biology (P50 GM076547, Leroy Hood, principal investigator), the Intramural Research Program of the National Institute of Mental Health (F.J.M.), U.S. Department of Veterans Affairs Merit Awards I01BX004062 and 101BX003631 (T.D.G.), the University of Luxembourg–Institute for Systems Biology Strategic Partnership (Leroy Hood, principal investigator), a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation (S.A.A.), and seed funding from the University of Maryland School of Medicine (S.A.A.). Data and biomaterials were collected as part of 11 projects (Study 40) that participated in the NIMH Bipolar Disorder Genetics Initiative (MH59545, MH059534, MH59533, MH59553, MH60068, MH059548, MH59535, MH59567, MH059556, and 1Z01MH002810-01), which was also supported by NIH Grants P50CA89392, from the National Cancer Institute, and 5K02DA021237, from the National Institute of Drug Abuse. We thank the Coriell Institute for providing DNA samples. We thank the staff of the University of Maryland Veterinary Resources and at the Mutant Mouse Resource and Research Center at UC Davis for assistance in maintaining and archiving the DaoG130V/+ knock-in mouse line. We thank the Genomics Resource Center at the University of Maryland School of Medicine for RNA sequencing. Most importantly, we thank the families who have participated in and contributed to these studies.

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Authors and Affiliations

  1. Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA

    Naushaba Hasin, Robert Lease, Rediet T. Oshone, Elizabeth M. Humphries & Seth A. Ament

  2. Program in Neuroscience and Training Program in Integrative Membrane Biology, University of Maryland School of Medicine, Baltimore, MD, USA

    Lace M. Riggs

  3. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

    Lace M. Riggs, Todd D. Gould & Seth A. Ament

  4. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Tatyana Shekhtman & John R. Kelsoe

  5. Institute for Systems Biology, Seattle, WA, USA

    Justin Ashworth & Jared C. Roach

  6. Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Robert Lease

  7. Program in Molecular Epidemiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Elizabeth M. Humphries

  8. Department of Psychiatry, Rush University Medical College, Chicago, IL, USA

    Judith A. Badner

  9. Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, UK

    Pippa A. Thomson

  10. Department of Psychiatry, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    David C. Glahn

  11. Department of Translational Genomics, University of Southern California, Los Angeles, CA, USA

    David W. Craig

  12. Departments of Biochemistry and Molecular Biology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Howard J. Edenberg

  13. Departments of Psychiatry and Human Genetics, University of Chicago, Chicago, IL, USA

    Elliot S. Gershon

  14. Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA

    Francis J. McMahon

  15. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA

    John I. Nurnberger

  16. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Peter P. Zandi

  17. Departments of Pharmacology and Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Todd D. Gould

  18. Veterans Affairs Maryland Health Care System, Baltimore, MD, USA

    Todd D. Gould

Authors
  1. Naushaba Hasin
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  2. Lace M. Riggs
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  20. Seth A. Ament
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Contributions

Conceptualization: NH, SAA. Investigation: NH, LMR, TS, JA, RL, RTO, EMH, JB, PT, JCR, and SAA. Funding acquisition: SAA, JRK, and PPZ. Supervision: DCG, DWC, HWE, ESG, FJM, JIN, PPZ, JRK, JCR, TDG, and SAA. Writing – original draft: NH, LMR, SAA. Writing – review & editing: all authors.

Corresponding author

Correspondence to Seth A. Ament.

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Competing interests

Dr. Nurnberger is an investigator for Janssen. All other authors declare that they have no competing interests. The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

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Hasin, N., Riggs, L.M., Shekhtman, T. et al. Rare variants implicate NMDA receptor signaling and cerebellar gene networks in risk for bipolar disorder. Mol Psychiatry 27, 3842–3856 (2022). https://doi.org/10.1038/s41380-022-01609-4

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