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Thalamic connectivity measured with fMRI is associated with a polygenic index predicting thalamo-prefrontal gene co-expression

  • Linda A. Antonucci
  • Pasquale Di Carlo
  • Roberta Passiatore
  • Marco Papalino
  • Anna Monda
  • Nicola Amoroso
  • Sabina Tangaro
  • Paolo Taurisano
  • Antonio Rampino
  • Fabio Sambataro
  • Teresa Popolizio
  • Alessandro Bertolino
  • Giulio Pergola
  • Giuseppe BlasiEmail author
Original Article
  • 43 Downloads

Abstract

The functional connectivity between thalamic medio-dorsal nucleus (MD) and cortical regions, especially the dorsolateral prefrontal cortex (DLPFC), is implicated in attentional processing and is anomalous in schizophrenia, a brain disease associated with polygenic risk and attentional deficits. However, the molecular and genetic underpinnings of thalamic connectivity anomalies are unclear. Given that gene co-expression across brain areas promotes synchronous interregional activity, our aim was to investigate whether coordinated expression of genes relevant to schizophrenia in MD and DLPFC may reflect thalamic connectivity anomalies in an attention-related network including the DLPFC. With this aim, we identified in datasets of post-mortem prefrontal mRNA expression from healthy controls a gene module with robust overrepresentation of genes with coordinated MD-DLPFC expression and enriched for schizophrenia genes according to the largest genome-wide association study to date. To link this gene cluster with imaging phenotypes, we computed a Polygenic Co-Expression Index (PCI) combining single-nucleotide polymorphisms predicting module co-expression. Finally, we investigated the association between PCI and thalamic functional connectivity during attention through fMRI Independent Component Analysis in 265 healthy participants. We found that PCI was positively associated with connectivity strength of a thalamic region overlapping with the MD within an attention brain circuit. These findings identify a novel association between schizophrenia-related genes and thalamic functional connectivity. Furthermore, they highlight the association between gene expression co-regulation and brain connectivity, such that genes with coordinated MD-DLPFC expression are associated with coordinated activity between the same brain regions. We suggest that gene co-expression is a plausible mechanism underlying biological phenotypes of schizophrenia.

Keywords

Coordinated gene expression Independent Component Analysis Medio-dorsal nucleus DLPFC fMRI Schizophrenia 

Notes

Acknowledgements

Data acquisition was made possible by Riccarda Lomuscio, Dr. Marina Mancini, Rita Masellis, Dr. Annamaria Porcelli, Dr. Tiziana Quarto, Dr. Raffaella Romano, and Dr. Leonardo Fazio (Department of Basic Medical Science, Neuroscience, and Sense Organs, University of Bari Aldo Moro).

Funding

This work was supported by a “Capitale Umano ad Alta Qualificazione” Grant by Fondazione Con Il Sud and by the “Ricerca Finalizzata” Grant (number: PE-2011-02347951) awarded to Alessandro Bertolino, as well as by a Hoffmann-La Roche Collaboration Grant awarded to Giulio Pergola. This project has received funding from the European Union Seventh Framework Programme for research, technological development and demonstration under Grant agreement no. 602450. This paper reflects only the author’s views and the European Union is not liable for any use that may be made of the information contained therein. The funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

Alessandro Bertolino is a stockholder of Hoffmann-La Roche Ltd. He has also received lecture fees from Otsuka, Jannsen, Lundbeck, and consultant fees from Biogen. Giulio Pergola has been the academic supervisor of a Hoffmann-La Roche collaboration Grant (years 2015–2016) that funds his and Antonio Rampino’s salary. Antonio Rampino has received travel fees from Lundbeck. All other authors declare no biomedical financial interests and no potential conflicts of interest.

Ethical statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

429_2019_1843_MOESM1_ESM.docx (521 kb)
Supplementary material 1 (DOCX 520 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Linda A. Antonucci
    • 1
    • 2
  • Pasquale Di Carlo
    • 1
  • Roberta Passiatore
    • 1
  • Marco Papalino
    • 1
  • Anna Monda
    • 1
  • Nicola Amoroso
    • 3
    • 4
  • Sabina Tangaro
    • 4
  • Paolo Taurisano
    • 1
  • Antonio Rampino
    • 1
    • 5
  • Fabio Sambataro
    • 6
  • Teresa Popolizio
    • 7
  • Alessandro Bertolino
    • 1
    • 5
  • Giulio Pergola
    • 1
  • Giuseppe Blasi
    • 1
    • 5
    Email author
  1. 1.Department of Basic Medical Science, Neuroscience and Sense OrgansUniversity of Bari Aldo MoroBariItaly
  2. 2.Department of Education Science, Psychology and Communication ScienceUniversity of Bari Aldo MoroBariItaly
  3. 3.Dipartimento Interateneo di Fisica “M. Merlin”University of Bari Aldo MoroBariItaly
  4. 4.Istituto Nazionale di Fisica NucleareNaplesItaly
  5. 5.Psychiatry UnitBari University HospitalBariItaly
  6. 6.Department of PsychiatryUniversity of UdineUdineItaly
  7. 7.IRCCS “Casa Sollievo della Sofferenza”San Giovanni RotondoItaly

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