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Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis
V. Niemsiri, SB. Rosenthal, CM. Nievergelt, AX. Maihofer, MC. Marchetto, R. Santos, T. Shekhtman, N. Alliey-Rodriguez, A. Anand, Y. Balaraman, WH. Berrettini, H. Bertram, KE. Burdick, JR. Calabrese, CV. Calkin, C. Conroy, WH. Coryell, A....
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, N.I.H., Extramural
Grantová podpora
R01 MH095741
NIMH NIH HHS - United States
UL1 TR001442
NCATS NIH HHS - United States
U19 MH106434
NIMH NIH HHS - United States
U01 MH092758
NIMH NIH HHS - United States
T32 MH018399
NIMH NIH HHS - United States
NLK
ProQuest Central
od 2000-01-01 do Před 1 rokem
Open Access Digital Library
od 1997-01-01
Health & Medicine (ProQuest)
od 2000-01-01 do Před 1 rokem
Psychology Database (ProQuest)
od 2000-01-01 do Před 1 rokem
- MeSH
- antimanika farmakologie terapeutické užití MeSH
- bipolární porucha * farmakoterapie genetika MeSH
- celogenomová asociační studie * metody MeSH
- farmakogenetika metody MeSH
- fokální adheze * účinky léků genetika MeSH
- genomika metody MeSH
- genové regulační sítě * účinky léků genetika MeSH
- indukované pluripotentní kmenové buňky účinky léků metabolismus MeSH
- lidé MeSH
- lithium * farmakologie terapeutické užití MeSH
- multiomika MeSH
- neurony metabolismus účinky léků MeSH
- sloučeniny lithia farmakologie terapeutické užití MeSH
- stanovení celkové genové exprese metody MeSH
- transkriptom * genetika účinky léků MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.
Department of Anthropology University of California San Diego La Jolla CA USA
Department of Clinical Medicine University of Bergen Bergen Norway
Department of Psychiatry and Behavioral Neuroscience Northwestern University Chicago IL USA
Department of Psychiatry and Behavioral Neuroscience University of Chicago Chicago IL USA
Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore MD USA
Department of Psychiatry and Medical Neuroscience Dalhousie University Halifax NS Canada
Department of Psychiatry Brigham and Women's Hospital Harvard Medical School Boston MA USA
Department of Psychiatry Dalhousie University Halifax NS Canada
Department of Psychiatry Indiana University School of Medicine Indianapolis IN USA
Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston MA USA
Department of Psychiatry The Mayo Clinic Rochester MN USA
Department of Psychiatry University of California San Diego La Jolla CA USA
Department of Psychiatry University of Iowa Iowa City IA USA
Department of Psychiatry University of Michigan Ann Arbor MI USA
Department of Psychiatry University of Pennsylvania Philadelphia PA USA
Department of Translational Genomics University of Southern California Los Angeles CA USA
Institute for Genomic Medicine University of California San Diego La Jolla CA USA
Laboratory of Genetics Salk Institute for Biological Studies La Jolla CA USA
Mood Disorders Program Case Western Reserve University School of Medicine Cleveland OH USA
Mood Disorders Program University Hospitals Cleveland Medical Center Cleveland OH USA
National Institute of Mental Health Klecany Czech Republic
Psychiatry Service VA San Diego Healthcare System San Diego CA USA
Citace poskytuje Crossref.org
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