In a groundbreaking advance in neuropsychiatric research, scientists have leveraged integrative multi-omics approaches to unveil novel insights into the genetic and cellular underpinnings of attention-deficit/hyperactivity disorder (ADHD). This complex neurodevelopmental condition, characterized by persistent patterns of hyperactivity, impulsivity, and inattentiveness, has long posed challenges for researchers due to the elusive nature of its genetic architecture. The latest study synthesizes vast genomic datasets with cutting-edge transcriptomic profiling, focusing on gene expression dynamics during early human brain development to dissect the molecular landscape that may predispose individuals to ADHD.
Over recent years, genome-wide association studies (GWAS) have mapped numerous genetic loci implicated in ADHD, yet a puzzling aspect has persisted: the majority of these loci reside in non-coding regions of the genome. These non-coding variants complicate efforts to pinpoint causal genes or biological pathways, as their regulatory roles are often subtle and context-dependent. To surmount this barrier, the current research utilized a summary data-based Mendelian randomization (SMR) framework to integrate expression quantitative trait loci (eQTL) data with GWAS findings. This method offers a powerful strategy to link genetic variation with gene expression alterations, thereby illuminating potential mechanistic pathways.
The eQTL data harnessed in this investigation came from diverse sources, including bulk post-mortem brain tissues, fetal brain samples, and single-cell transcriptomic profiles derived from both induced pluripotent stem cell (iPSC)-derived neurons and post-mortem neural cells. Such breadth of data allowed for a comprehensive developmental perspective, capturing gene expression shifts from early embryonic stages through later maturation. By cross-referencing these multi-dimensional datasets with ADHD-associated genetic variants, the researchers identified pivotal genes influencing disease risk.
Notably, two genes—LSM6 and RPS26—emerged as significantly associated with ADHD when examining eQTL data from fetal brain samples and iPSC-derived neuronal cells. Both genes exhibited heightened expression during critical early developmental windows, suggesting that disruptions in their regulation might interfere with foundational neurodevelopmental processes. In contrast, gene expression patterns derived from adult post-mortem brain tissues displayed lower activity of these loci prior to the typical window of ADHD symptom onset, underscoring the importance of temporal context in understanding disease etiology.
The identification of LSM6 and RPS26 is particularly intriguing given their biological functions. LSM6 plays a role in RNA splicing and turnover, processes essential for accurate gene expression regulation during neural development. RPS26 encodes a ribosomal protein implicated in protein synthesis—another fundamental mechanism for cellular growth and differentiation. Alterations in these pathways could feasibly disrupt neuronal circuit formation or synaptic plasticity, contributing to ADHD pathology.
In addition to gene-level insights, the study delved into cell-type specificity to uncover which neural populations harbor genetic vulnerabilities. Utilizing SNP-based heritability partitioning and cell-type enrichment analyses, the researchers found a predominant enrichment of ADHD-associated genetic signal in excitatory glutamatergic neurons. These neurons, known for their crucial role in modulating cortical excitatory-inhibitory balance, are integral to attentional control and cognitive processing—domains disrupted in ADHD. Conversely, glial cells, which support neural function and maintain homeostasis, exhibited comparatively lower enrichment, suggesting that neuronal pathways may be the primary mediators of genetic risk.
This cellular focus is significant, as it converges with emerging frameworks that emphasize developmental timing and cell-type specificity in neuropsychiatric disorders. The authors propose that genetic variants influencing gene expression in fetal excitatory neurons could have downstream effects on brain circuit formation, potentially predisposing individuals to ADHD symptoms that manifest during childhood. Such findings align with developmental models positing that early perturbations in neural networks set the stage for later behavioral phenotypes.
Methodologically, the study exemplifies the power of integrative multi-omics analyses to disentangle complex genetic contributions. By merging genetic association data with detailed expression profiles from single cells and bulk tissues, the researchers captured a nuanced view of gene regulation across both space and time. This holistic approach transcends the limitations of single-data-type studies and furthers the field’s understanding of how genetic architecture interacts with developmental programs.
The implications for ADHD research and treatment are considerable. Illuminating the precise genes and cell types involved in early neurodevelopment offers novel targets for therapeutic intervention. Moreover, understanding the temporal window during which genetic risk factors exert influence could refine strategies for early detection and prevention. Such insights pave the way for personalized medicine approaches tailored to an individual’s genetic and developmental profile.
Beyond ADHD, the study underscores a broader paradigm shift in psychiatric genetics, where integrating developmental biology with genome-scale data illuminates mechanisms obscured in adult brain tissue analyses. These approaches promise to reveal the hidden layers of neurodevelopmental disorders, enabling breakthroughs that were previously unattainable with traditional methodologies.
Importantly, the identification of specific genetic variants affecting gene expression deepens the mechanistic understanding of ADHD’s pathogenesis. It suggests that genetic risk does not simply reside in static DNA sequences but manifests dynamically through gene regulatory networks that evolve during brain development. Hence, future research integrating epigenetic, proteomic, and functional genomic data alongside multi-omics could further unravel the intricate biology behind ADHD.
In conclusion, this pioneering study charts a detailed map linking genetic variation, gene expression, cell-type specificity, and developmental timing in the context of ADHD. By highlighting LSM6 and RPS26 and implicating excitatory neurons during early fetal life, it advances our grasp of the disorder’s molecular origins. These findings illuminate pathways that may one day be harnessed to improve clinical outcomes for millions affected by ADHD worldwide.
Subject of Research: Attention-deficit/hyperactivity disorder genetics and neurodevelopmental gene expression
Article Title: Integrative multi-omics data from early development to identify the genes and cell types underlying attention-deficit/hyperactivity disorder
Article References:
Jiao, S., Bao, L., Lu, X. et al. Integrative multi-omics data from early development to identify the genes and cell types underlying attention-deficit/hyperactivity disorder.
BMC Psychiatry 25, 741 (2025). https://doi.org/10.1186/s12888-025-07209-0
Image Credits: AI Generated
DOI: https://doi.org/10.1186/s12888-025-07209-0
