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

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. ZinkAlessandro Bertolino, Oliver D. Howes, Karen F. Berman, Daniel R. Weinberger^*, Giulio Pergola^*

^*Corresponding author for this work

NIHR Maudsley Biomedical Research Centre (BRC)

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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.

Original language	English
Article number	3342
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-47456-5
Publication status	Published - 30 Apr 2024

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Sportelli, L., Eisenberg, D. P., Passiatore, R., D’Ambrosio, E., Antonucci, L. A., Bettina, J. S., Chen, Q., Goldman, A. L., Gregory, M. D., Griffiths, K., Hyde, T. M., Kleinman, J. E., Pardiñas, A. F., Parihar, M., Popolizio, T., Rampino, A., Shin, J. H., Veronese, M., Ulrich, W. S., ... Pergola, G. (2024). Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo. Nature Communications, 15(1), Article 3342. https://doi.org/10.1038/s41467-024-47456-5

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title = "Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo",

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.",

author = "Leonardo Sportelli and Eisenberg, {Daniel P.} and Roberta Passiatore and Enrico D{\textquoteright}Ambrosio and Antonucci, {Linda A.} and Bettina, {Jasmine S.} and Qiang Chen and Goldman, {Aaron L.} and Gregory, {Michael D.} and Kira Griffiths and Hyde, {Thomas M.} and Kleinman, {Joel E.} and Pardi{\~n}as, {Antonio F.} and Madhur Parihar and Teresa Popolizio and Antonio Rampino and Shin, {Joo Heon} and Mattia Veronese and Ulrich, {William S.} and Zink, {Caroline F.} and Alessandro Bertolino and Howes, {Oliver D.} and Berman, {Karen F.} and Weinberger, {Daniel R.} and Giulio Pergola",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = apr,

day = "30",

doi = "10.1038/s41467-024-47456-5",

language = "English",

volume = "15",

journal = "Nature Communications",

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Sportelli, L, Eisenberg, DP, Passiatore, R, D’Ambrosio, E, Antonucci, LA, Bettina, JS, Chen, Q, Goldman, AL, Gregory, MD, Griffiths, K, Hyde, TM, Kleinman, JE, Pardiñas, AF, Parihar, M, Popolizio, T, Rampino, A, Shin, JH, Veronese, M, Ulrich, WS, Zink, CF, Bertolino, A, Howes, OD, Berman, KF, Weinberger, DR & Pergola, G 2024, 'Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo', Nature Communications, vol. 15, no. 1, 3342. https://doi.org/10.1038/s41467-024-47456-5

TY - JOUR

T1 - Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo

AU - Sportelli, Leonardo

AU - Eisenberg, Daniel P.

AU - Passiatore, Roberta

AU - D’Ambrosio, Enrico

AU - Antonucci, Linda A.

AU - Bettina, Jasmine S.

AU - Chen, Qiang

AU - Goldman, Aaron L.

AU - Gregory, Michael D.

AU - Griffiths, Kira

AU - Hyde, Thomas M.

AU - Kleinman, Joel E.

AU - Pardiñas, Antonio F.

AU - Parihar, Madhur

AU - Popolizio, Teresa

AU - Rampino, Antonio

AU - Shin, Joo Heon

AU - Veronese, Mattia

AU - Ulrich, William S.

AU - Zink, Caroline F.

AU - Bertolino, Alessandro

AU - Howes, Oliver D.

AU - Berman, Karen F.

AU - Weinberger, Daniel R.

AU - Pergola, Giulio

PY - 2024/4/30

Y1 - 2024/4/30

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-024-47456-5

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AN - SCOPUS:85191858859

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3342

ER -

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

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