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Published Online: 1 December 2020

Association of Missense Mutation in FOLH1 With Decreased NAAG Levels and Impaired Working Memory Circuitry and Cognition

Caroline F. Zink, Ph.D., Peter B. Barker, D.Phil., Akira Sawa, M.D., Daniel R. Weinberger, M.D., Min Wang, Ph.D., Henry Quillian, B.S., William S. Ulrich, M.S., Qiang Chen, Ph.D., Andrew E. Jaffe, Ph.D., Joel E. Kleinman, M.D., Ph.D., Thomas M. Hyde, M.D., Ph.D., Greer E. Prettyman, B.S., Mellissa Giegerich, M.S.W., Kayla Carta, B.S., Marcus van Ginkel, B.S., and Kristin L. Bigos, Ph.D. [email protected]Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 177, Number 12
https://doi.org/10.1176/appi.ajp.2020.19111152
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Abstract

Objective:

Altering the metabotropic glutamate receptor 3 (mGluR3) by pharmacology or genetics is associated with differences in learning and memory in animals and humans. GRM3 (the gene coding for mGluR3) is also genome-wide associated with risk for schizophrenia. The neurotransmitter N-acetyl-aspartyl-glutamate (NAAG) is the selective endogenous agonist of mGluR3, and increasing NAAG may improve cognition. Glutamate carboxypeptidase II (GCPII), coded by the gene folate hydrolase 1 (FOLH1), regulates the amount of NAAG in the synapse. The goal of this study was to determine the relationship between FOLH1, NAAG levels, measures of human cognition, and neural activity associated with cognition.

Methods:

The effects of genetic variation in FOLH1 on mRNA expression in human brain and NAAG levels using 7-T magnetic resonance spectroscopy (MRS) were measured. NAAG levels and FOLH1 genetic variation were correlated with measures of cognition in subjects with psychosis and unaffected subjects. Additionally, FOLH1 genetic variation was correlated with neural activity during working memory, as measured by functional MRI (fMRI).

Results:

A missense mutation in FOLH1 (rs202676 G allele) was associated with increased FOLH1 mRNA in the dorsolateral prefrontal cortex of brains from unaffected subjects and schizophrenia patients. This FOLH1 variant was associated with decreased NAAG levels in unaffected subjects and patients with psychosis. NAAG levels were positively correlated with visual memory performance. Carriers of the FOLH1 variant associated with lower NAAG levels had lower IQ scores. Carriers of this FOLH1 variant had less efficient cortical activity during working memory.

Conclusions:

These data show that higher NAAG levels are associated with better cognition, suggesting that increasing NAAG levels through FOLH1/GCPII inhibition may improve cognition. Additionally, NAAG levels measured by MRS and cortical efficiency during working memory measured by fMRI have the potential to be neuroimaging biomarkers for future clinical trials.

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Supplementary Material

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 177 • Number 12 • December 01, 2020
Pages: 1129 - 1139

History

Received: 12 November 2019
Revision received: 27 April 2020
Revision received: 9 June 2020
Accepted: 7 July 2020
Published online: 1 December 2020
Published in print: December 01, 2020

Keywords

  1. Genetics
  2. Cognition
  3. Mutations
  4. N-Acetyl-Aspartyl-Glutamate

Authors

Affiliations

Caroline F. Zink, Ph.D.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Peter B. Barker, D.Phil.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Akira Sawa, M.D.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Daniel R. Weinberger, M.D.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Min Wang, Ph.D.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Henry Quillian, B.S.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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William S. Ulrich, M.S.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Qiang Chen, Ph.D.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Andrew E. Jaffe, Ph.D.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Joel E. Kleinman, M.D., Ph.D.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Thomas M. Hyde, M.D., Ph.D.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Greer E. Prettyman, B.S.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Mellissa Giegerich, M.S.W.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Kayla Carta, B.S.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Marcus van Ginkel, B.S.
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Kristin L. Bigos, Ph.D. [email protected]
Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).
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Notes

Send correspondence to Dr. Bigos ([email protected]).

Competing Interests

The authors report no financial relationships with commercial interests.

Funding Information

National Institute of Mental Healthhttp://dx.doi.org/10.13039/100000025: MH092443, MH094268, MH105660, MH107730
Lieber Institute for Brain Development:
Mitsubishi Tanabe Pharma Corporationhttp://dx.doi.org/10.13039/501100012351:
National Institute on Drug Abusehttp://dx.doi.org/10.13039/100000026: DA040127
Supported by direct funding from the Lieber Institute for Brain Development and NIH (grants MH092443, MH094268, DA040127, MH105660, and MH107730 to Dr. Sawa). A portion of subject recruitment costs was supported by the Mitsubishi Tanabe Pharma Corporation.

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