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Association of variants in DRD2 and GRM3 with motor and cognitive function in first-episode psychosis

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Abstract

Similar smooth pursuit eye tracking dysfunctions are present across psychotic disorders. They include pursuit initiation and maintenance deficits that implicate different functional brain systems. This candidate gene study examined psychosis-related genotypes regulating dopamine and glutamate neurotransmission in relation to these pursuit deficits. One hundred and thirty-eight untreated first-episode patients with a psychotic disorder were genotyped for four markers in DRD2 and four markers in GRM3. The magnitude of eye movement abnormality in patients was defined in relation to performance of matched healthy controls (N = 130). Eighty three patients were followed after 6 weeks of antipsychotic treatment. At baseline, patients with a −141C deletion in DRD2 rs1799732 had slower initiation eye velocity and longer pursuit latency than CC insertion carriers. Further, GRM3 rs274622_CC carriers had poorer pursuit maintenance than T-carriers. Antipsychotic treatment resulted in prolonged pursuit latency in DRD2 rs1799732_CC insertion carriers and a decline in pursuit maintenance in GRM3 rs6465084_GG carriers. The present study demonstrates for the first time that neurophysiological measures of motor and neurocognitive deficits in patients with psychotic disorders have different associations with genes regulating dopamine and glutamate systems, respectively. Alterations in striatal D2 receptor activity through the −141C Ins/Del polymorphism could contribute to pursuit initiation deficits in psychotic disorders. Alterations in GRM3 coding for the mGluR3 protein may impair pursuit maintenance by compromising higher perceptual and cognitive processes that depend on optimal glutamate signaling in corticocortical circuits. DRD2 and GRM3 genotypes also selectively modulated the severity of adverse motor and neurocognitive changes resulting from antipsychotic treatment.

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Acknowledgments

We thank Drs. Ovidio DeLeon, Gretchen Haas, Robert Marvin, Debra Montrose, Cherise Rosen, Hugo Solari, Peter Weiden and the clinical core staff of the Center for the Neuroscience of Mental Disorders (MH45156, David Lewis MD, Director) for their contributions to diagnostic and psychopathological assessments. We note with appreciation the general statistical genetics input to our studies by Dr. Judith Badner. This study was supported by National Institute of Health (NIH) grants MH083888, MH062134, MH083126, MH45156, MH63480, RR024153, CTSA Grant UL1TR000050 and NIH/NCRR/GCRC Grant RR00056, Janssen Pharmaceuticals and the Alexander von Humboldt Foundation. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of NIH. Main results of this study have been presented as a poster at the World Congress of Psychiatric Genetics 2012 in Hamburg, Germany.

Conflict of interest

Dr Sweeney is a consultant to Roche, Pfizer, Takeda, Bristol-Myers Squibb and Eli Lilly. Dr. Bishop has received research support from Ortho-McNeil Janssen. Drs Lencer, Harris, Reilly, Patel, Kittles, Prasad, Nimgaonkar and Keshavan report no biomedical financial interests or potential conflicts of interest.

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, University of Muenster, Albert Schweitzer Campus 1, Geb. A9, 48149, Muenster, Germany

    Rebekka Lencer

  2. Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, USA

    Jeffrey R. Bishop & Shitalben Patel

  3. College of Medicine, University of Illinois at Chicago, Chicago, USA

    Margret S. H. Harris & Rick Kittles

  4. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, USA

    James L. Reilly

  5. Department of Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, USA

    Konasale M. Prasad & Vishwajit L. Nimgaonkar

  6. Department of Human Genetics, University of Pittsburgh, Pittsburgh, USA

    Vishwajit L. Nimgaonkar

  7. Department of Psychiatry, Harvard Medical School, Boston, USA

    Matcheri S. Keshavan

  8. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, USA

    John A. Sweeney

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  1. Rebekka Lencer
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  2. Jeffrey R. Bishop
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  3. Margret S. H. Harris
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  10. John A. Sweeney
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Correspondence to Rebekka Lencer.

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Lencer, R., Bishop, J.R., Harris, M.S.H. et al. Association of variants in DRD2 and GRM3 with motor and cognitive function in first-episode psychosis. Eur Arch Psychiatry Clin Neurosci 264, 345–355 (2014). https://doi.org/10.1007/s00406-013-0464-6

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