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

Autor: Niemsiri V; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Rosenthal SB; Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, CA, USA., Nievergelt CM; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Maihofer AX; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Marchetto MC; Department of Anthropology, University of California, San Diego, La Jolla, CA, USA.; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA., Santos R; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA.; University of Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1261266, Laboratory of Dynamics of Neuronal Structure in Health and Disease, Paris, France., Shekhtman T; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Alliey-Rodriguez N; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.; Department of Psychiatry and Behavioral Neuroscience, Northwestern University, Chicago, IL, USA., Anand A; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Balaraman Y; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA., Berrettini WH; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA., Bertram H; Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA., Burdick KE; Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Calabrese JR; Mood Disorders Program, Case Western Reserve University School of Medicine, Cleveland, OH, USA.; Mood Disorders Program, University Hospitals Cleveland Medical Center, Cleveland, OH, USA., Calkin CV; Department of Psychiatry and Medical Neuroscience, Dalhousie University, Halifax, NS, Canada., Conroy C; Mood Disorders Program, Case Western Reserve University School of Medicine, Cleveland, OH, USA.; Mood Disorders Program, University Hospitals Cleveland Medical Center, Cleveland, OH, USA., Coryell WH; Department of Psychiatry, University of Iowa, Iowa City, IA, USA., DeModena A; Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, USA., Eyler LT; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Feeder S; Department of Psychiatry, The Mayo Clinic, Rochester, MN, USA., Fisher C; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA., Frazier N; Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA., Frye MA; Department of Psychiatry, The Mayo Clinic, Rochester, MN, USA., Gao K; Mood Disorders Program, Case Western Reserve University School of Medicine, Cleveland, OH, USA.; Mood Disorders Program, University Hospitals Cleveland Medical Center, Cleveland, OH, USA., Garnham J; Department of Psychiatry, Dalhousie University, Halifax, NS, Canada., Gershon ES; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA., Goes FS; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA., Goto T; Mood Disorders Program, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Harrington GJ; Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA., Jakobsen P; Norment, Division of Psychiatry, Haukeland University Hospital and Department of Clinical medicine, University of Bergen, Bergen, Norway., Kamali M; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA., Kelly M; Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA., Leckband SG; Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, USA., Lohoff FW; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA., McCarthy MJ; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., McInnis MG; Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA., Craig D; Department of Translational Genomics, University of Southern California, Los Angeles, CA, USA., Millett CE; Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Mondimore F; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA., Morken G; Division of Mental Health Care, St Olavs University Hospital, and Department of Mental Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway., Nurnberger JI; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.; Medical and Molecular Genetics, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA., Donovan CO; Department of Psychiatry, Dalhousie University, Halifax, NS, Canada., Øedegaard KJ; Norment, Division of Psychiatry, Haukeland University Hospital and Department of Clinical medicine, University of Bergen, Bergen, Norway., Ryan K; Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA., Schinagle M; Mood Disorders Program, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Shilling PD; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Slaney C; Department of Psychiatry, Dalhousie University, Halifax, NS, Canada., Stapp EK; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA., Stautland A; Department of Clinical Medicine, University of Bergen, Bergen, Norway., Tarwater B; Department of Psychiatry, University of Iowa, Iowa City, IA, USA., Zandi PP; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA., Alda M; Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.; National Institute of Mental Health, Klecany, Czech Republic., Fisch KM; Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, CA, USA.; Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Diego, La Jolla, CA, USA., Gage FH; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA., Kelsoe JR; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. jkelsoe@health.ucsd.edu.; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA. jkelsoe@health.ucsd.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 Jan; Vol. 29 (1), pp. 6-19. Date of Electronic Publication: 2023 Mar 29.
DOI: 10.1038/s41380-022-01909-9
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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