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Am J Med Genet B Neuropsychiatr Genet. 2018 Oct;177(7):658-664. doi: 10.1002/ajmg.b.32663. Epub 2018 Oct 14.

Convergent analysis of genome-wide genotyping and transcriptomic data suggests association of zinc finger genes with lithium response in bipolar disorder.

Author information

1
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.
2
Advanced Sequencing Facility, the Francis Crick Institute, London NW1 1AT, UK.
3
Unit of Clinical Pharmacology, University Hospital of Cagliari, Cagliari, Italy.
4
Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cagliari, Italy.
5
Institute of Psychiatric Phenomics and Genomics (IPPG), Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany.
6
U.S. Department of Health & Human Services, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.

Abstract

Lithium is the mainstay treatment in bipolar disorder (BD) for its effectiveness in the acute phases of illness and in prevention of recurrences. Lithium's mechanism of action is complex, and while it modulates the function of hundreds of molecular targets, most of these effects could be unspecific and not relevant for its clinical efficacy. In this study, we applied an integrated analytical approach using genome-wide expression and genotyping data from BD patients to identify lithium-responsive genes that may serve as biomarkers of its efficacy. To this purpose, we tested the effect of treatment with lithium chloride 1 mM on the transcriptome of lymphoblasts from 10 lithium responders (LR) and 10 nonresponders (NR) patients and identified genes significantly influenced by the treatment exclusively in LR. These findings were integrated with gene-based analysis on genome-wide genotyping data from an extended sample of 205 BD patients characterized for lithium response. The expression of 29 genes was significantly changed by lithium exclusively in LR. Gene-based analysis showed that two of these genes, zinc finger protein 429 (ZNF429) and zinc finger protein 493 (ZNF493), were also significantly associated with lithium response. Validation with quantitative real-time polymerase chain reaction confirmed the lithium-induced downregulation of ZNF493 in LR (p = .036). Using convergent analyses of genome-wide expression and genotyping data, we identified ZNF493 as a potential lithium-responsive target that may be involved in modulating lithium efficacy in BD. To our knowledge, this is the first evidence supporting the involvement of zinc finger proteins in lithium response.

KEYWORDS:

ZNF493; biomarker; bipolar disorder; lithium; pharmacogenomics

PMID:
30318722
PMCID:
PMC6230310
[Available on 2019-10-14]
DOI:
10.1002/ajmg.b.32663

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