Transcriptomic and Metabolomic Analysis of the Caudate and Putamen in ADHD
- 1State University of New York at Buffalo
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous neurodevelopmental disorder that typically manifests in childhood; however, transcriptomic studies have inadequately accounted for age of onset and subtype, with cohorts largely comprising of adults. To address this gap, we established a stringently phenotyped ADHD cohort (up to 19 years; clinically diagnosed combined and inattentive-type ADHD) and integrated postmortem caudate and putamen bulk RNA-seq, LC-MS metabolomics, MEGENA gene co-expression analysis, and cross-study comparison. We identified 279 up- and 35 downregulated DEGs in the caudate and 110 up- and 89 downregulated DEGs in the putamen. The combined caudate-putamen metabolomic analysis revealed dopamine dysregulation (1.68-fold reduction) and dysregulation of four additional metabolites. Enrichment analysis revealed shared molecular signatures involving immune responses, ATP metabolism and calcium ion-dependent signaling, with region-specific differences in the direction of alteration. Neuronal homeostasis, and protein stress showed suppression in the putamen, along with activation of neurotransmitter reuptake, whereas CSF circulation and ECM organization were activated in the caudate, with suppression in CNS myelination, and signs of ventricular perturbations. MEGENA identified 26 ADHD-associated caudate modules and 33 putamen modules. These modules captured canonical synaptic and neuronal-circuitry pathways alongside cellular differentiation, metabolism, and cell-survival processes. FGD1 emerged as a candidate caudate hub gene among the neuronal modules. Cross-study comparison analysis suggested that molecular alterations in ADHD may be age-dependent. Additionally, assessing levels of 76 potential risk genes identified by a large ADHD GWAS study one ARTN exhibited dysregulated levels in putamen and none in caudate. Together, these findings reveal brain-region-specific molecular dysregulation in ADHD across pathways extending beyond canonical neurotransmission to immune, differentiation, and energy-metabolic processes, along with novel evidence of perturbations in the understudied lateral ventricles.
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BibTeX
@misc{patel2026transcriptomic,
title = {{Transcriptomic and Metabolomic Analysis of the Caudate and Putamen in ADHD}},
author = {R. Patel and S. Wang and E. Deshmukh and S. Fajen and J. Williams},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.06.764706},
url = {https://www.biorxiv.org/content/10.64898/2026.11.06.764706v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Transcriptomic and Metabolomic Analysis of the Caudate and Putamen in ADHD
AU - R. Patel
AU - S. Wang
AU - E. Deshmukh
AU - S. Fajen
AU - J. Williams
PY - 2026
DA - 2026/11/06
PB - bioRxiv
DO - 10.64898/2026.11.06.764706
UR - https://www.biorxiv.org/content/10.64898/2026.11.06.764706v1
AB - Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous neurodevelopmental disorder that typically manifests in childhood; however, transcriptomic studies have inadequately accounted for age of onset and subtype, with cohorts largely comprising of adults. To address this gap, we established a stringently phenotyped ADHD cohort (up to 19 years; clinically diagnosed combined and inattentive-type ADHD) and integrated postmortem caudate and putamen bulk RNA-seq, LC-MS metabolomics, MEGENA gene co-expression analysis, and cross-study comparison. We identified 279 up- and 35 downregulated DEGs in the caudate and 110 up- and 89 downregulated DEGs in the putamen. The combined caudate-putamen metabolomic analysis revealed dopamine dysregulation (1.68-fold reduction) and dysregulation of four additional metabolites. Enrichment analysis revealed shared molecular signatures involving immune responses, ATP metabolism and calcium ion-dependent signaling, with region-specific differences in the direction of alteration. Neuronal homeostasis, and protein stress showed suppression in the putamen, along with activation of neurotransmitter reuptake, whereas CSF circulation and ECM organization were activated in the caudate, with suppression in CNS myelination, and signs of ventricular perturbations. MEGENA identified 26 ADHD-associated caudate modules and 33 putamen modules. These modules captured canonical synaptic and neuronal-circuitry pathways alongside cellular differentiation, metabolism, and cell-survival processes. FGD1 emerged as a candidate caudate hub gene among the neuronal modules. Cross-study comparison analysis suggested that molecular alterations in ADHD may be age-dependent. Additionally, assessing levels of 76 potential risk genes identified by a large ADHD GWAS study one ARTN exhibited dysregulated levels in putamen and none in caudate. Together, these findings reveal brain-region-specific molecular dysregulation in ADHD across pathways extending beyond canonical neurotransmission to immune, differentiation, and energy-metabolic processes, along with novel evidence of perturbations in the understudied lateral ventricles.
ER -