Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo

Leonardo Sportelli; Daniel P Eisenberg; Roberta Passiatore; Enrico D'Ambrosio; Linda A Antonucci; Jasmine S Bettina; Qiang Chen; Aaron L Goldman; Michael D Gregory; Kira Griffiths; Thomas M Hyde; Joel E Kleinman; Antonio F Pardiñas; Madhur Parihar; Teresa Popolizio; Antonio Rampino; Joo Heon Shin; Mattia Veronese; William S Ulrich; Caroline F Zink; Alessandro Bertolino; Oliver D Howes; Karen F Berman; Daniel R Weinberger; Giulio Pergola

doi:10.1038/s41467-024-47456-5

Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo

Nat Commun. 2024 Apr 30;15(1):3342. doi: 10.1038/s41467-024-47456-5.

Authors

Leonardo Sportelli^#^{1

2}, Daniel P Eisenberg^#³, Roberta Passiatore², Enrico D'Ambrosio^{2

4}, Linda A Antonucci², Jasmine S Bettina³, Qiang Chen¹, Aaron L Goldman¹, Michael D Gregory³, Kira Griffiths^{4

5}, Thomas M Hyde^{1

6

7}, Joel E Kleinman^{1

7}, Antonio F Pardiñas⁸, Madhur Parihar¹, Teresa Popolizio⁹, Antonio Rampino^{2

10}, Joo Heon Shin¹, Mattia Veronese^{11

12}, William S Ulrich¹, Caroline F Zink¹³, Alessandro Bertolino^{2

10}, Oliver D Howes⁴, Karen F Berman³, Daniel R Weinberger^{14

15

16

17

18}, Giulio Pergola^{19

20

21}

Affiliations

¹ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
² Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy.
³ Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, NIH, DHHS, Bethesda, MD, USA.
⁴ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
⁵ Holmusk Technologies, New York, NY, USA.
⁶ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
⁹ Radiology Department, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
¹⁰ Azienda Ospedaliero Universitaria Consorziale Policlinico, Bari, Italy.
¹¹ Department of Information Engineering, University of Padua, Padua, Italy.
¹² Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
¹³ Baltimore Research and Education Foundation, Baltimore, MD, USA.
¹⁴ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. [email protected].
¹⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁶ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁷ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁸ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁹ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. [email protected].
²⁰ Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy. [email protected].
²¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].

^# Contributed equally.

Abstract

The polygenic architecture of schizophrenia implicates several molecular pathways involved in synaptic function. However, it is unclear how polygenic risk funnels through these pathways to translate into syndromic illness. Using tensor decomposition, we analyze gene co-expression in the caudate nucleus, hippocampus, and dorsolateral prefrontal cortex of post-mortem brain samples from 358 individuals. We identify a set of genes predominantly expressed in the caudate nucleus and associated with both clinical state and genetic risk for schizophrenia that shows dopaminergic selectivity. A higher polygenic risk score for schizophrenia parsed by this set of genes predicts greater dopamine synthesis in the striatum and greater striatal activation during reward anticipation. These results translate dopamine-linked genetic risk variation into in vivo neurochemical and hemodynamic phenotypes in the striatum that have long been implicated in the pathophysiology of schizophrenia.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Caudate Nucleus / metabolism
Corpus Striatum* / metabolism
Dopamine* / biosynthesis
Dopamine* / metabolism
Dorsolateral Prefrontal Cortex / metabolism
Female
Genetic Predisposition to Disease
Hippocampus / metabolism
Humans
Male
Middle Aged
Multifactorial Inheritance
Reward
Schizophrenia* / genetics
Schizophrenia* / metabolism
Signal Transduction

Substances

Dopamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding