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

  • Zhongshan Cheng
    Affiliations
    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
    Affiliations
    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
    Affiliations
    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
    Affiliations
    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
    Affiliations
    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
    Correspondence
    Address correspondence to Joel Gelernter, M.D., VA CT 116A2, 950 Campbell Avenue, West Haven, CT 06516.
    Affiliations
    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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      Abstract

      Background

      Opioid dependence (OD) is at epidemic levels in the United States. Genetic studies can provide insight into its biology.

      Methods

      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.

      Results

      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.

      Conclusions

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

      Keywords

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      References

        • Mistry C.J.
        • Bawor M.
        • Desai D.
        • Marsh D.C.
        • Samaan Z.
        Genetics of opioid dependence: A review of the genetic contribution to opioid dependence.
        Curr Psychiatry Rev. 2014; 10: 156-167
        • Gelernter J.
        • Kranzler H.R.
        • Sherva R.
        • Koesterer R.
        • Almasy L.
        • Zhao H.
        • et al.
        Genome-wide association study of opioid dependence: Multiple associations mapped to calcium and potassium pathways.
        Biol Psychiatry. 2014; 76: 66-74
        • Nelson E.C.
        • Agrawal A.
        • Heath A.C.
        • Bogdan R.
        • Sherva R.
        • Zhang B.
        • et al.
        Evidence of CNIH3 involvement in opioid dependence.
        Mol Psychiatry. 2016; 21: 608-614
        • Smith A.H.
        • Jensen K.P.
        • Li J.
        • Nunez Y.
        • Farrer L.A.
        • Hakonarson H.
        • et al.
        Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1.
        Mol Psychiatry. 2017; 22: 346-352
        • Chang C.C.
        • Chow C.C.
        • Tellier L.C.
        • Vattikuti S.
        • Purcell S.M.
        • Lee J.J.
        Second-generation PLINK: Rising to the challenge of larger and richer datasets.
        Gigascience. 2015; 4: 7
        • Abecasis G.R.
        • Altshuler D.
        • Auton A.
        • Brooks L.D.
        • Durbin R.M.
        • et al.
        • 1000 Genomes Project Consortium
        A map of human genome variation from population-scale sequencing.
        Nature. 2010; 467: 1061-1073
        • Price A.L.
        • Patterson N.J.
        • Plenge R.M.
        • Weinblatt M.E.
        • Shadick N.A.
        • Reich D.
        Principal components analysis corrects for stratification in genome-wide association studies.
        Nat Genet. 2006; 38: 904-909
        • Sherva R.
        • Wang Q.
        • Kranzler H.
        • Zhao H.
        • Koesterer R.
        • Herman A.
        • et al.
        Genome-wide association study of cannabis dependence severity, novel risk variants, and shared genetic risks.
        JAMA Psychiatry. 2016; 73: 472-480
        • Radmanesh F.
        • Devan W.J.
        • Anderson C.D.
        • Rosand J.
        • Falcone G.J.
        • Alzheimer’s Disease Neuroimaging I
        Accuracy of imputation to infer unobserved APOE epsilon alleles in genome-wide genotyping data.
        Eur J Hum Genet. 2014; 22: 1239-1242
        • Zhou X.
        • Stephens M.
        Genome-wide efficient mixed-model analysis for association studies.
        Nat Genet. 2012; 44: 821-824
        • Bierut L.J.
        • Strickland J.R.
        • Thompson J.R.
        • Afful S.E.
        • Cottler L.B.
        Drug use and dependence in cocaine dependent subjects, community-based individuals, and their siblings.
        Drug Alcohol Depend. 2008; 95: 14-22
        • Edenberg H.J.
        The collaborative study on the genetics of alcoholism: An update.
        Alcohol Res Health. 2002; 26: 214-218
        • Howie B.N.
        • Donnelly P.
        • Marchini J.
        A flexible and accurate genotype imputation method for the next generation of genome-wide association studies.
        PLoS Genet. 2009; 5e1000529
        • Risueno A.
        • Roson-Burgo B.
        • Dolnik A.
        • Hernandez-Rivas J.M.
        • Bullinger L.
        • De Las Rivas J.
        A robust estimation of exon expression to identify alternative spliced genes applied to human tissues and cancer samples.
        BMC Genomics. 2014; 15: 879
        • Hernandez D.G.
        • Nalls M.A.
        • Moore M.
        • Chong S.
        • Dillman A.
        • Trabzuni D.
        • et al.
        Integration of GWAS SNPs and tissue specific expression profiling reveal discrete eQTLs for human traits in blood and brain.
        Neurobiol Dis. 2012; 47: 20-28
        • Barrett T.
        • Wilhite S.E.
        • Ledoux P.
        • Evangelista C.
        • Kim I.F.
        • Tomashevsky M.
        • et al.
        NCBI GEO: Archive for functional genomics data sets-update.
        Nucleic Acids Res. 2013; 41: D991-D995
        • Ramasamy A.
        • Trabzuni D.
        • Guelfi S.
        • Varghese V.
        • Smith C.
        • Walker R.
        • et al.
        Genetic variability in the regulation of gene expression in ten regions of the human brain.
        Nat Neurosci. 2014; 17: 1418-1428
        • Cheng Z.
        • Chu H.
        • Fan Y.
        • Li C.
        • Song Y.Q.
        • Zhou J.
        • et al.
        PExFInS: An integrative post-GWAS explorer for functional indels and SNPs.
        Sci Rep. 2015; 5: 17302
        • Korostynski M.
        • Piechota M.
        • Kaminska D.
        • Solecki W.
        • Przewlocki R.
        Morphine effects on striatal transcriptome in mice.
        Genome Biol. 2007; 8: R128
        • Sean D.
        • Meltzer P.S.
        GEOquery: A bridge between the gene expression omnibus (GEO) and BioConductor.
        Bioinformatics. 2007; 23: 1846-1847
        • Choudhury K.
        • McQuillin A.
        • Puri V.
        • Pimm J.
        • Datta S.
        • Thirumalai S.
        • et al.
        A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia.
        Am J Hum Genet. 2007; 80: 664-672
        • Jonsson E.G.
        • Saetre P.
        • Vares M.
        • Andreou D.
        • Larsson K.
        • Timm S.
        • et al.
        DTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: An association study.
        Neuropsychobiology. 2009; 59: 142-150
        • Demontis D.
        • Nyegaard M.
        • Buttenschon H.N.
        • Hedemand A.
        • Pedersen C.B.
        • Grove J.
        • et al.
        Association of GRIN1 and GRIN2A-D with schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk.
        Am J Med Genet B Neuropsychiatr Genet. 2011; 156B: 913-922
        • Tsai S.J.
        • Hong C.J.
        • Cheng C.Y.
        • Liao D.L.
        • Liou Y.J.
        Association study of polymorphisms in post-synaptic density protein 95 (PSD-95) with schizophrenia.
        J Neural Transm (Vienna). 2007; 114: 423-426
        • Pereira A.C.
        • Gray J.D.
        • Kogan J.F.
        • Davidson R.L.
        • Rubin T.G.
        • Okamoto M.
        • et al.
        Age and Alzheimer’s disease gene expression profiles reversed by the glutamate modulator riluzole.
        Mol Psychiatry. 2017; 22: 296-305
        • Torrico B.
        • Fernandez-Castillo N.
        • Hervas A.
        • Mila M.
        • Salgado M.
        • Rueda I.
        • et al.
        Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability.
        Eur J Hum Genet. 2015; 23: 1694-1701
        • Okochi T.
        • Kishi T.
        • Ikeda M.
        • Kitajima T.
        • Kinoshita Y.
        • Kawashima K.
        • et al.
        Genetic association analysis of NRG1 with methamphetamine-induced psychosis in a Japanese population.
        Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33: 903-905
        • Steinberg S.
        • de Jong S.
        • Andreassen O.A.
        • Werge T.
        • Borglum A.D.
        • Mors O.
        • et al.
        Common variants at VRK2 and TCF4 conferring risk of schizophrenia.
        Hum Mol Genet. 2011; 20: 4076-4081
        • Tassew N.G.
        • Charish J.
        • Seidah N.G.
        • Monnier P.P.
        SKI-1 and Furin generate multiple RGMa fragments that regulate axonal growth.
        Dev Cell. 2012; 22: 391-402
        • Monnier P.P.
        • Sierra A.
        • Macchi P.
        • Deitinghoff L.
        • Andersen J.S.
        • Mann M.
        • et al.
        RGM is a repulsive guidance molecule for retinal axons.
        Nature. 2002; 419: 392-395
        • Hata K.
        • Fujitani M.
        • Yasuda Y.
        • Doya H.
        • Saito T.
        • Yamagishi S.
        • et al.
        RGMa inhibition promotes axonal growth and recovery after spinal cord injury.
        J Cell Biol. 2006; 173: 47-58
        • Kyoto A.
        • Hata K.
        • Yamashita T.
        Synapse formation of the cortico-spinal axons is enhanced by RGMa inhibition after spinal cord injury.
        Brain Res. 2007; 1186: 74-86
        • Matsunaga E.
        • Tauszig-Delamasure S.
        • Monnier P.P.
        • Mueller B.K.
        • Strittmatter S.M.
        • Mehlen P.
        • et al.
        RGM and its receptor neogenin regulate neuronal survival.
        Nat Cell Biol. 2004; 6: 749-755
        • Schwab J.M.
        • Monnier P.P.
        • Schluesener H.J.
        • Conrad S.
        • Beschorner R.
        • Chen L.
        • et al.
        Central nervous system injury-induced repulsive guidance molecule expression in the adult human brain.
        Arch Neurol. 2005; 62: 1561-1568
        • Satoh J.
        • Tabunoki H.
        • Ishida T.
        • Saito Y.
        • Arima K.
        Accumulation of a repulsive axonal guidance molecule RGMa in amyloid plaques: A possible hallmark of regenerative failure in Alzheimer’s disease brains.
        Neuropathol Appl Neurobiol. 2013; 39: 109-120
        • Bossers K.
        • Meerhoff G.
        • Balesar R.
        • van Dongen J.W.
        • Kruse C.G.
        • Swaab D.F.
        • et al.
        Analysis of gene expression in Parkinson’s disease: Possible involvement of neurotrophic support and axon guidance in dopaminergic cell death.
        Brain Pathol. 2009; 19: 91-107
        • Nohra R.
        • Beyeen A.D.
        • Guo J.P.
        • Khademi M.
        • Sundqvist E.
        • Hedreul M.
        • et al.
        RGMA and IL21R show association with experimental inflammation and multiple sclerosis.
        Genes Immun. 2010; 11: 279-293
        • Demicheva E.
        • Cui Y.F.
        • Bardwell P.
        • Barghorn S.
        • Kron M.
        • Meyer A.H.
        • et al.
        Targeting repulsive guidance molecule a to promote regeneration and neuroprotection in multiple sclerosis.
        Cell Rep. 2015; 10: 1887-1898
        • Mundo E.
        • Tharmalingham S.
        • Neves-Pereira M.
        • Dalton E.J.
        • Macciardi F.
        • Parikh S.V.
        • et al.
        Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder.
        Mol Psychiatry. 2003; 8: 241-245
        • Ge X.
        • Qiu Y.
        • Loh H.H.
        • Law P.Y.
        GRIN1 regulates micro-opioid receptor activities by tethering the receptor and G protein in the lipid raft.
        J Biol Chem. 2009; 284: 36521-36534
        • Jo D.G.
        • Lee J.Y.
        • Hong Y.M.
        • Song S.
        • Mook-Jung I.
        • Koh J.Y.
        • et al.
        Induction of pro-apoptotic calsenilin/DREAM/KChIP3 in Alzheimer’s disease and cultured neurons after amyloid-beta exposure.
        J Neurochem. 2004; 88: 604-611
        • Wang J.C.
        • Foroud T.
        • Hinrichs A.L.
        • Le N.X.
        • Bertelsen S.
        • Budde J.P.
        • et al.
        A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53.
        Mol Psychiatry. 2013; 18: 1218-1224
        • Luo Z.H.
        • Alvarado G.F.
        • Hatsukami D.K.
        • Johnson E.O.
        • Bierut L.J.
        • Breslau N.
        Race differences in nicotine dependence in the Collaborative Genetic study of Nicotine Dependence (COGEND).
        Nicotine Tob Res. 2008; 10: 1223-1230
        • Ward L.D.
        • Kellis M.
        HaploReg v4: Systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease.
        Nucleic Acids Res. 2016; 44: D877-D881