Identification of Risk Genes for Attention-Deficit/Hyperactivity Disorder During Early Human Brain Development - 27/08/25
Abstract |
Objective |
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with high heritability. A total of 27 genome-wide significant loci for ADHD were previously identified through genome-wide association studies (GWASs), but the identification of risk genes that confer susceptibility to ADHD has remained largely unexplored.
Method |
As ADHD is a neurodevelopmental disorder, we integrated human brain prenatal gene and transcript expression weight data (n = 120) and ADHD GWAS summary statistics (n = 225,534; 38,691 cases and 186,843 controls) to perform a transcriptome-wide association study (TWAS) by FUSION (an analytic suite).
Results |
Our analysis identified 10 genes, including LSM6, HYAL3, METTL15, RPS26, LRRC37A15P, RP11-142I20.1, ABCB9, AP006621.5, AC000068.5 , and PDXDC1 , that are significantly associated with ADHD, along with 8 transcripts of 7 genes. We also conducted TWAS analysis using CommonMind Consortium (CMC) adult brain gene and gene-splicing expression weights (n = 452), which highlighted several risk genes that showed associations with ADHD in both prenatal and postnatal stages, such as LSM6 and HYAL3 .
Conclusion |
Overall, our TWAS of ADHD, by integrating human prenatal brain transcriptome and ADHD GWAS results, uncovered the cis-effects of gene/transcript regulation that are predicted to be associated with ADHD. By combining colocalization and FOCUS fine-mapping analysis, we further unraveled potential causal candidate risk genes. The risk genes/transcripts that we identified in this study can serve as a valuable resource for further investigation of the disease mechanisms underlying ADHD.
Plain language summary |
By analyzing the combined genetic data from over 225,000 people and genes related to brain development in this transcriptome-wide association study, the authors identified 10 significant genes linked to ADHD. These genes are active during early brain growth, affecting how brain cells communicate.
Le texte complet de cet article est disponible en PDF.Key words : ADHD, GWAS, FUSION, TWAS, prenatal brain
Plan
| Work on this article was supported by Hubei Provincial Natural Science Foundation of China (2024AFB1022 to J.L.). |
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| The authors have reported the use of AI or AI-assisted technologies: use of monica ChatGPT AI Assistant to help check English writing; only for editing language use. |
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| Code Availability: The authors have made their scripts publicly available through the following link: JAACAP_ADHD . |
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| Data Sharing: Data were generated as part of the CommonMind Consortium (CMC) supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffmann-La Roche Ltd., and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881, AG02219, AG05138, MH06692, R01MH110921, R01MH109677, R01MH109897, U01MH103392, and contract HHSN271201300031C through IRP NIMH. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories, and the NIMH Human Brain Collection Core. CMC Leadership: Panos Roussos, Joseph Buxbaum, Andrew Chess, Schahram Akbarian, Vahram Haroutunian (Icahn School of Medicine at Mount Sinai), Bernie Devlin, David Lewis (University of Pittsburgh), Raquel Gur, Chang-Gyu Hahn (University of Pennsylvania), Enrico Domenici (University of Trento), Mette A. Peters, Solveig Sieberts (Sage Bionetworks), Thomas Lehner, Stefano Marenco, Barbara K. Lipska (NIMH). |
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| Disclosure: Ming-Gang Deng, Xiuxiu Zhou, Xiaoyan Li, and Jiewei Liu have reported no biomedical financial interests or potential conflicts of interest. |
Vol 64 - N° 9
P. 1080-1091 - septembre 2025 Retour au numéro
Article précédent
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