Convergent functional genomics of genome-wide association data for bipolar disorder: Comprehensive identification of candidate genes, pathways and mechanisms

Authors

  • H. Le-Niculescu,

    1. Laboratory of Neurophenomics, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
    2. INBRAIN, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
    3. Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
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  • S.D. Patel,

    1. Laboratory of Neurophenomics, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
    2. INBRAIN, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
    3. Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
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  • M. Bhat,

    1. Laboratory of Neurophenomics, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
    2. Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
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  • R. Kuczenski,

    1. Department of Psychiatry, UC San Diego, La Jolla, California
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  • S.V. Faraone,

    1. Department of Psychiatry, SUNY Upstate Medical University, Syracuse, New York
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  • M.T. Tsuang,

    1. Department of Psychiatry, UC San Diego, La Jolla, California
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  • F.J. McMahon,

    1. Mood and Anxiety Disorders Branch, NIMH, Bethesda, Maryland
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  • N.J. Schork,

    1. Scripps Genomic Medicine, The Scripps Research Institute, La Jolla, California
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  • J.I. Nurnberger Jr.,

    1. Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
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  • A.B. Niculescu III

    Corresponding author
    1. Laboratory of Neurophenomics, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
    2. INBRAIN, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
    3. Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
    • Assistant Professor of Psychiatry and Medical Neuroscience, Indiana University School of Medicine; Staff Psychiatrist, Indianapolis VA Medical Center, Director, INBRAIN and Laboratory of Neurophenomics, Institute of Psychiatric Research, 791 Union Drive, Indianapolis, IN 46202-4887.
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  • Please cite this article as follows: Le-Niculescu H, Patel SD, Bhat M, Kuczenski R, Faraone SV, Tsuang MT, McMahon FJ, Schork NJ, Nurnberger Jr JI, Niculescu AB. 2009. Convergent Functional Genomics of Genome-Wide Association Data for Bipolar Disorder: Comprehensive Identification of Candidate Genes, Pathways and Mechanisms. Am J Med Genet Part B 150B:155–181.

Abstract

Given the mounting convergent evidence implicating many more genes in complex disorders such as bipolar disorder than the small number identified unambiguously by the first-generation Genome-Wide Association studies (GWAS) to date, there is a strong need for improvements in methodology. One strategy is to include in the next generation GWAS larger numbers of subjects, and/or to pool independent studies into meta-analyses. We propose and provide proof of principle for the use of a complementary approach, convergent functional genomics (CFG), as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach. With the CFG approach, the integration of genetics with genomics, of human and animal model data, and of multiple independent lines of evidence converging on the same genes offers a way of extracting signal from noise and prioritizing candidates. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder, yielding a series of novel (such as Klf12, Aldh1a1, A2bp1, Ak3l1, Rorb, Rora) and previously known (such as Bdnf, Arntl, Gsk3b, Disc1, Nrg1, Htr2a) candidate genes, blood biomarkers, as well as a comprehensive identification of pathways and mechanisms. These become prime targets for hypothesis driven follow-up studies, new drug development and personalized medicine approaches. © 2008 Wiley-Liss, Inc.

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