. 2019 Sep 30:291:34-41.

doi: 10.1016/j.pscychresns.2019.07.005. Epub 2019 Jul 19.

The effect of a genetic variant at the schizophrenia associated AS3MT/BORCS7 locus on striatal dopamine function: A PET imaging study

Affiliations

¹ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; Psychiatric Neuroscience Group, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
² Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX37 JX, UK.
³ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
⁴ Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
⁵ Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK; Translational Psychiatry, Research Department of Mental Health Neuroscience, Division of Psychiatry, University College London, Maple House, 149 Tottenham Court Road, London W1T 7NF, UK; Clinical Psychopharmacology Unit, Research Department of Clinical, Educational & Health Psychology, University College London, 1-19 Torrington Place, London WC1E 7HB, UK; NIHR University College London Hospitals Biomedical Research Centre, Maple House, 149 Tottenham Court Road, London W1T 7DN, UK.
⁶ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; South London and Maudsley NHS Trust, London, UK.
⁷ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK.
⁸ Center for Neural Science, New York University, New York 10003, USA.
⁹ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK; South London and Maudsley NHS Trust, London, UK. Electronic address: oliver.howes@kcl.ac.uk.

PMID: 31386983
PMCID: PMC7099976
DOI: 10.1016/j.pscychresns.2019.07.005

The effect of a genetic variant at the schizophrenia associated AS3MT/BORCS7 locus on striatal dopamine function: A PET imaging study

Enrico D'Ambrosio et al. Psychiatry Res Neuroimaging. 2019.

. 2019 Sep 30:291:34-41.

doi: 10.1016/j.pscychresns.2019.07.005. Epub 2019 Jul 19.

Authors

Affiliations

¹ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; Psychiatric Neuroscience Group, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
² Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX37 JX, UK.
³ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
⁴ Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
⁵ Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK; Translational Psychiatry, Research Department of Mental Health Neuroscience, Division of Psychiatry, University College London, Maple House, 149 Tottenham Court Road, London W1T 7NF, UK; Clinical Psychopharmacology Unit, Research Department of Clinical, Educational & Health Psychology, University College London, 1-19 Torrington Place, London WC1E 7HB, UK; NIHR University College London Hospitals Biomedical Research Centre, Maple House, 149 Tottenham Court Road, London W1T 7DN, UK.
⁶ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; South London and Maudsley NHS Trust, London, UK.
⁷ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK.
⁸ Center for Neural Science, New York University, New York 10003, USA.
⁹ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK; South London and Maudsley NHS Trust, London, UK. Electronic address: oliver.howes@kcl.ac.uk.

PMID: 31386983
PMCID: PMC7099976
DOI: 10.1016/j.pscychresns.2019.07.005

Abstract

One of the most statistically significant loci to result from large-scale GWAS of schizophrenia is 10q24.32. However, it is still unclear how this locus is involved in the pathoaetiology of schizophrenia. The hypothesis that presynaptic dopamine dysfunction underlies schizophrenia is one of the leading theories of the pathophysiology of the disorder. Supporting this, molecular imaging studies show evidence for elevated dopamine synthesis and release capacity. Thus, altered dopamine function could be a potential mechanism by which this genetic variant acts to increase the risk of schizophrenia. We therefore tested the hypothesis that the 10q24.32 region confers genetic risk for schizophrenia through an effect on striatal dopamine function. To this aim we investigated the in vivo relationship between a GWAS schizophrenia-associated SNP within this locus and dopamine synthesis capacity measured using [¹⁸F]-DOPA PET in healthy controls. 92 healthy volunteers underwent [¹⁸F]-DOPA PET scans to measure striatal dopamine synthesis capacity (indexed as K_i^cer) and were genotyped for the SNP rs7085104. We found a significant association between rs7085104 genotype and striatal K_i^cer. Our findings indicate that the mechanism mediating the 10q24.32 risk locus for schizophrenia could involve altered dopaminergic function. Future studies are needed to clarify the neurobiological pathway implicated in this association.

Keywords: 10q24.32; Dopamine synthesis capacity; Imaging; PET; Psychosis; Schizophrenia; Striatum.

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Conflict of interest statement

Financial Disclosures and conflict of interests

Professor Howes has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Astra-Zeneca, Autifony, BMS, Eli Lilly, Heptares, Janssen, Lundbeck, Lyden-Delta, Otsuka, Servier, Sunovion, Rand and Roche. Neither Professor Howes nor his family have been employed by or have holdings/a financial stake in any biomedical company.

Dr D'Ambrosio reported no biomedical financial interests or potential conflicts of interest.

Dr Dahoun reported no biomedical financial interests or potential conflicts of interest.

Dr Pardiñas reported no biomedical financial interests or potential conflicts of interest.

Dr Veronese reported no biomedical financial interests or potential conflicts of interest.

Dr Bloomfield reported no biomedical financial interests or potential conflicts of interest.

Dr Jauhar reported no biomedical financial interests or potential conflicts of interest.

Dr Bonoldi reported no biomedical financial interests or potential conflicts of interest.

Dr Rogdaki reported no biomedical financial interests or potential conflicts of interest.

Dr Froudist-Walsh reported no biomedical financial interests or potential conflicts of interest.

Professor Walters reported no biomedical financial interests or potential conflicts of interest.

Figures

**Figure 1. Effect of AS3MT rs7085104 on whole striatum K_i^cer**

**Figure 2. Exploratory analyses: effect of AS3MT rs7085104 on K_i^cer in the different striatal subdivisions**

See this image and copyright information in PMC

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The effect of a genetic variant at the schizophrenia associated AS3MT/BORCS7 locus on striatal dopamine function: A PET imaging study

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The effect of a genetic variant at the schizophrenia associated AS3MT/BORCS7 locus on striatal dopamine function: A PET imaging study

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