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Article Dans Une Revue Molecular Psychiatry Année : 2023

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

1 UC San Diego - University of California [San Diego]
2 CCBB - Center for Computational Biology and Bioinformatics [San Diego, USA]
3 The Salk Institute for Biological Studies
4 IPNP - U1266 Inserm - Institut de psychiatrie et neurosciences de Paris
5 University of Chicago
6 Northwestern University [Chicago, Ill. USA]
7 Massachusetts General Hospital [Boston]
8 HMS - Harvard Medical School [Boston]
9 Brigham and Women’s Hospital [Boston, MA]
10 Indiana University School of Medicine
11 University of Pennsylvania
12 University of Michigan [Ann Arbor]
13 UH Cleveland Medical Center - University Hospitals Case Medical Center
14 Case Western Reserve University [Cleveland]
15 Dalhousie University [Halifax]
16 University of Iowa [Iowa City]
17 VASDHS - VA San Diego Healthcare System [San Diego, CA, USA]
18 Mayo Clinic [Rochester]
19 JHU - Johns Hopkins University
20 Haukeland University Hospital
21 UiB - University of Bergen
22 Massachusetts General Hospital [Boston, MA, USA]
23 UC - University of California
24 USC - University of Southern California
25 St. Olav's University Hospital - St. Olavs Hospital HF
26 NTNU - Norwegian University of Science and Technology
27 Stark Neurosciences Research Institute
28 UC San Francisco - University of California [San Francisco]
29 Johns Hopkins Bloomberg School of Public Health [Baltimore]
30 NIMH - National Institute of Mental Health [Klecany, Czech Republic]
31 Center for Computational Biology and Bioinformatics
32 IFGM - INSTITUTE FOR GENOMIC MEDICINE [ San Diego, USA]
Cynthia V Calkin
Mark A Frye
Julie Garnham
Fernando S Goes
Marisa Kelly
Falk W Lohoff
Melvin G Mcinnis
Andrea Stautland
Fred H Gage

Résumé

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 (P hypergeometric = 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.
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Dates et versions

inserm-04118355 , version 1 (06-06-2023)

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Vipavee Niemsiri, Sara Brin Rosenthal, Caroline M Nievergelt, Adam X Maihofer, Maria C Marchetto, et al.. Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis. Molecular Psychiatry, 2023, ⟨10.1038/s41380-022-01909-9⟩. ⟨inserm-04118355⟩

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