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Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing

Molecular Psychiatry volume 19, pages 129–139 (2014)Cite this article

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Abstract

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.

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Acknowledgements

This work was supported by the Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania. Financial support is gratefully acknowledged from National Institutes of Health Grants (NIH K08MH080372 to FWL), NCRR (UL1 RR 024986), NIMH (P01 MH 42251, R25 MH 6374 and K23 MH 074459), NIDA (R01 DA 016423 and R01 DA 022520, and 026222 and 031579) and the Phil F Jenkins Research Fund.

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Authors and Affiliations

  1. Department of Psychiatry, Translational Research Laboratories, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    F W Lohoff, R Hodge, S Narasimhan, A Nall, T N Ferraro & G A Doyle

  2. Department of Psychiatry, Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA

    B J Mickey, M M Heitzeg, S A Langenecker & J-K Zubieta

  3. Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA

    R Bogdan, Y S Nikolova & A R Hariri

  4. Department of Psychology, Washington University in St Louis, St Louis, MO, USA

    R Bogdan

  5. 23andMe, Mountain View, CA, USA

    E Drabant

  6. Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA

    L Bevilacqua & D Goldman

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  1. F W Lohoff
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Correspondence to F W Lohoff.

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Competing interests

Dr Lohoff declares that he is named as one of the inventors of a patent involving human genetic VMAT1 variants (US Patent No. 7 736 852). Within the 3-year period before submission of the manuscript, Dr Mickey has received salary support from St Jude Medical for research unrelated to this manuscript, and Dr Zubieta has served as a paid consultant for Eli Lilly, Johnson & Johnson, Merck and Abbott for work unrelated to this manuscript. All remaining authors declare no conflict of interest.

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Lohoff, F., Hodge, R., Narasimhan, S. et al. Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing. Mol Psychiatry 19, 129–139 (2014). https://doi.org/10.1038/mp.2012.193

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