Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans

  • Zhongshan Cheng
    Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Massachusetts

    VA Connecticut Healthcare Center, West Haven, Massachusetts
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  • Hang Zhou
    Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Massachusetts

    VA Connecticut Healthcare Center, West Haven, Massachusetts
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  • Richard Sherva
    Departments of Neurology, Ophthalmology, Genetics & Genomics, Epidemiology, and Biostatistics, Boston University School of Medicine and School Public Health, Boston, Massachusetts
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  • Lindsay A. Farrer
    Departments of Neurology, Ophthalmology, Genetics & Genomics, Epidemiology, and Biostatistics, Boston University School of Medicine and School Public Health, Boston, Massachusetts
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  • Henry R. Kranzler
    Center for Studies of Addiction, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania

    Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania
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  • Joel Gelernter
    Address correspondence to Joel Gelernter, M.D., VA CT 116A2, 950 Campbell Avenue, West Haven, CT 06516.
    Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Massachusetts

    Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, Massachusetts

    VA Connecticut Healthcare Center, West Haven, Massachusetts
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      Opioid dependence (OD) is at epidemic levels in the United States. Genetic studies can provide insight into its biology.


      We completed an OD genome-wide association study in 3058 opioid-exposed European Americans, 1290 of whom met criteria for a DSM-IV diagnosis of OD. Analysis used DSM-IV criterion count.


      By meta-analysis of four cohorts, Yale-Penn 1 (n = 1388), Yale-Penn 2 (n = 996), Yale-Penn 3 (n = 98), and SAGE (Study of Addiction: Genetics and Environment) (n = 576), we identified a variant on chromosome 15, rs12442183, near RGMA, associated with OD (p = 1.3 × 10−8). The association was also genome-wide significant in Yale-Penn 1 taken individually and nominally significant in two of the other three samples. The finding was further supported in a meta-analysis of all available opioid-exposed African Americans (n = 2014 [1106 meeting DSM-IV OD criteria]; p = 3.0 × 10−3) from three cohorts; there was nominal significance in two of these samples. Thus, of seven subsamples examined in two populations, one was genome-wide significant, and four of six were nominally (or nearly) significant. RGMA encodes repulsive guidance molecule A, which is a central nervous system axon guidance protein. Risk allele rs12442183*T was correlated with higher expression of a specific RGMA transcript variant in frontal cortex (p = 2 × 10−3). After chronic morphine injection, the homologous mouse gene (Rgma) was upregulated in C57BL/6J striatum. Coexpression analysis of 1301 brain samples revealed that RGMA messenger RNA expression was associated with that of four genes implicated in other psychiatric disorders, including GRIN1.


      This is the first study to demonstrate an association of RGMA with OD. It provides a new lead into our understanding of OD pathophysiology.


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