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

Autor: Hasin N; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA., Riggs LM; Program in Neuroscience and Training Program in Integrative Membrane Biology, University of Maryland School of Medicine, Baltimore, MD, USA.; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA., Shekhtman T; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA., Ashworth J; Institute for Systems Biology, Seattle, WA, USA., Lease R; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.; Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA., Oshone RT; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA., Humphries EM; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.; Program in Molecular Epidemiology, University of Maryland School of Medicine, Baltimore, MD, USA., Badner JA; Department of Psychiatry, Rush University Medical College, Chicago, IL, USA., Thomson PA; Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, UK., Glahn DC; Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Craig DW; Department of Translational Genomics, University of Southern California, Los Angeles, CA, USA., Edenberg HJ; Departments of Biochemistry and Molecular Biology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA., Gershon ES; Departments of Psychiatry and Human Genetics, University of Chicago, Chicago, IL, USA., McMahon FJ; Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA., Nurnberger JI; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA., Zandi PP; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA., Kelsoe JR; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA., Roach JC; Institute for Systems Biology, Seattle, WA, USA., Gould TD; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.; Departments of Pharmacology and Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.; Veterans Affairs Maryland Health Care System, Baltimore, MD, USA., Ament SA; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA. sament@som.umaryland.edu.; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA. sament@som.umaryland.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2022 Sep; Vol. 27 (9), pp. 3842-3856. Date of Electronic Publication: 2022 May 11.
DOI: 10.1038/s41380-022-01609-4
Abstrakt: 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 (DAO G131V ). Heterologous expression of DAO G131V in human cells resulted in decreased DAO protein abundance and enzymatic activity. In a knock-in mouse model of DAO G131 , Dao G130V/+ , 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 Dao G130V 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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