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.

Center for Computational Biology and Bioinformatics University of California San Diego La Jolla CA USA

Department of Anthropology University of California San Diego La Jolla CA USA

Department of Clinical Medicine University of Bergen Bergen Norway

Department of Mental Health Johns Hopkins Bloomberg School of Public Health Johns Hopkins University Baltimore MD USA

Department of Obstetrics Gynecology and Reproductive Sciences University of California San Diego La Jolla CA USA

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

Division of Mental Health Care St Olavs University Hospital and Department of Mental Health Norwegian University of Science and Technology Trondheim Norway

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

Medical and Molecular Genetics Stark Neurosciences Research Institute Indiana University School of Medicine Indianapolis IN 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

Norment Division of Psychiatry Haukeland University Hospital and Department of Clinical medicine University of Bergen Bergen Norway

Psychiatry Service VA San Diego Healthcare System San Diego CA USA

University of Paris Institute of Psychiatry and Neuroscience of Paris INSERM U1261266 Laboratory of Dynamics of Neuronal Structure in Health and Disease Paris France

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