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Mapping the cortico-striatal transcriptome in attention deficit hyperactivity disorder

Molecular Psychiatry volume 28, pages 792–800 (2023)Cite this article

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Abstract

Despite advances in identifying rare and common genetic variants conferring risk for ADHD, the lack of a transcriptomic understanding of cortico-striatal brain circuitry has stymied a molecular mechanistic understanding of this disorder. To address this gap, we mapped the transcriptome of the caudate nucleus and anterior cingulate cortex in post-mortem tissue from 60 individuals with and without ADHD. Significant differential expression of genes was found in the anterior cingulate cortex and, to a lesser extent, the caudate. Significant downregulation emerged of neurotransmitter gene pathways, particularly glutamatergic, in keeping with models that implicate these neurotransmitters in ADHD. Consistent with the genetic overlap between mental disorders, correlations were found between the cortico-striatal transcriptomic changes seen in ADHD and those seen in other neurodevelopmental and mood disorders. This transcriptomic evidence points to cortico-striatal neurotransmitter anomalies in the pathogenesis of ADHD, consistent with current models of the disorder.

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Fig. 1: Differential gene expression results.
Fig. 2: Gene set enrichments analyses results.
Fig. 3: GSEA results for region-specific developmental sets in ACC and Caudate.
Fig. 4: Transdiagnostic transcriptomic analyses results.

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Data availability

Data are being deposited in NIMH Data Archive under Collection 3151, experiment 2056 (https://nda.nih.gov/edit_collection.html?id=3151), with the https://doi.org/10.15154/1527972.

Code availability

Code used for analyses and figures is deposited here: https://zenodo.org/badge/latestdoi/505945767, with the https://doi.org/10.5281/zenodo.6798439.

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Acknowledgements

The study was funded by the intramural programs of the NIMH and NHGRI: ZIC MH002903-15 to SM, ZIA HG200378-10 to PS, and ZIA HG000140 to ADB. We acknowledge the Pittsburgh and Maryland sites within the NIH funded Neurobiobank for the provision of tissues. We acknowledge Bhaskar Kolachana at the Human Brain Collection Core for preparing DNA for genotyping, Chandrasekharappa Settara and Frank Donovan at the Genomics Core for genotyping, and the NIH Intramural Sequencing Center. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).

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Authors and Affiliations

  1. Social and Behavioral Research Branch, Division of Intramural Research, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA

    Gustavo Sudre, Benjamin Jung & Philip Shaw

  2. Computational and Statistical Genomics Branch, Division of Intramural Research, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA

    Derek E. Gildea & Andreas D. Baxevanis

  3. Office of the Scientific Director, Division of Intramural Research, National Institute of Mental Health, NIH, Bethesda, MD, 20892, USA

    Gauri G. Shastri, Wendy Sharp & Philip Shaw

  4. Human Brain Collection Core, Division of Intramural Research, National Institute of Mental Health, NIH, Bethesda, MD, 20892, USA

    Qing Xu, Pavan K. Auluck & Stefano Marenco

  5. Translational and Functional Genomics Branch, Division of Intramural Research, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA

    Laura Elnitski

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  1. Gustavo Sudre
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  2. Derek E. Gildea
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Contributions

Contribution of each author to the manuscript: Study concept and design: GS, PS and SM. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: GS and PS. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: GS. Administrative, technical, or material support: GGS, WS, BJ, QX, PKA and LE. Study supervision: PS and SM. Obtained funding: PS, SM and ADB.

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Correspondence to Philip Shaw.

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Sudre, G., Gildea, D.E., Shastri, G.G. et al. Mapping the cortico-striatal transcriptome in attention deficit hyperactivity disorder. Mol Psychiatry 28, 792–800 (2023). https://doi.org/10.1038/s41380-022-01844-9

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