title: Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing.
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.
authors: Translational Research Laboratories, Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: F W
authors: FW
authors: Lohoff
authors: Translational Research Laboratories, Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: R
authors: R
authors: Hodge
authors: Translational Research Laboratories, Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: S
authors: S
authors: Narasimhan
authors: Translational Research Laboratories, Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: A
authors: A
authors: Nall
authors: Translational Research Laboratories, Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: T N
authors: TN
authors: Ferraro
authors: Department of Psychiatry, Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors: B J
authors: BJ
authors: Mickey
authors: Department of Psychiatry, Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors: M M
authors: MM
authors: Heitzeg
authors: Department of Psychiatry, Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors: S A
authors: SA
authors: Langenecker
authors: Department of Psychiatry, Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors: J-K
authors: JK
authors: Zubieta
authors: 1] Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA [2] Department of Psychology, Washington University in St Louis, St Louis, MO, USA.
authors: R
authors: R
authors: Bogdan
authors: Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA.
authors: Y S
authors: YS
authors: Nikolova
authors: 23andMe, Mountain View, CA, USA.
authors: E
authors: E
authors: Drabant
authors: Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA.
authors: A R
authors: AR
authors: Hariri
authors: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
authors: L
authors: L
authors: Bevilacqua
authors: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
authors: D
authors: D
authors: Goldman
authors: Translational Research Laboratories, Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: G A
authors: GA
authors: Doyle
mesh_terms: D000293:Adolescent; D000342:Affective Symptoms / Q000235:genetics* / Q000473:pathology; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D004644:Emotions / Q000502:physiology*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D014162:Transfection; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D015306:Biogenic Monoamines; D050493:Vesicular Monoamine Transport Proteins