Normative Model-based Morphological Phenotypic Heterogeneity and Associated Cellular Gene Transcript
Poster No:
275
Submission Type:
Abstract Submission
Authors:
Fanyu Zhang1, Hao Wu1, Lin Liu1, Yilu Li1, Chunyan Wang1, Pan Wang1, Bharat Biswal2
Institutions:
1University of Electronic Science and Technology of China, Chengdu, Sichuan, China, 2New Jersey Institute of Technology, Newark, NJ
First Author:
Co-Author(s):
Introduction:
Attention-deficit/hyperactivity disorder (ADHD) is a genetic developmental disorder with heterogeneous phenotypes (DSM-5, 2013). The brain morphological changes in ADHD were inconsistent and influenced by sex in individuals with traditional phenotypes (Rasmussen et al., 2004). Our objective is to reveal the potentially refined phenotype of ADHD accompanied by sexually morphological changes and its cellularly genetic transcription mechanism.
Methods:
We used structural magnetic resonance imaging data of 197 individuals with ADHD and 182 age- and sex-matched healthy controls. The residuals of gray matter volume between actual values of individuals with ADHD and predicted values by the normative model were estimated (Shan et al., 2022) and decomposed into multiple factors using the non-negative matrix factorization (Chen et al., 2019; Han et al., 2023). We further analyzed each factor composition influenced by age and sex differences, as well as its related cellular mechanism of gene transcription (Zhang et al., 2024).
Results:
Gray matter volume residuals were refined into four phenotypes (positive factor 1, PF1; positive factor 2, PF2; negative factor 1, NF1; and negative factor 2, NF2). Male with ADHD exhibited lower W values (factor composition) in NF2 than that in female with ADHD (two-tailed Mann-Whitney U = 2715, pFDR < 0.05). Genes related to PF1 were not recognized. Factor-related genes and ADHD risk genes were mainly enriched in the regulation of cell projection organization and post-synapse (NF1), protein kinase binding and post-synapse (NF2), glutamatergic synapse and kinase binding (PF2) (pFDR < 0.05). The cellular enrichment results showed that the function of post-synapse in excitatory/inhibitory neurons were enriched in all the three factors, including NF1, NF2 and PF2 (pFDR < 0.05).
Figure 1. The sexual differences of factor composition in negative disease factor 2. The distribution of W-values in male and female individuals with ADHD after age and site regression (two-tailed Mann-Whitney U tests, pFDR < 0.05). ADHD, attention-deficit/hyperactivity disorder; FDR, false discovery rates; NF2, negative disease factor 2.
Figure 2. Functional enrichment of gene transcripts related to the negative disease factor 2 of ADHD. A, Two gene lists, including the ADHD risk genes and PLS1+ gene list (related to the 5% z-values and cluster size > 150 voxels), jointly participate in the gene transcription process. B, The expression of overlapped genes between the PLS1+ gene list above and cellular genes, and the enrichment of these overlapped genes in 7 typical cells. ADHD, attention-deficit/hyperactivity disorder; FDR, false discovery rates; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; PLS, the partial least squares; PLS1+, the first positive principal component of PLS regression.
Figure 1. The sexual differences of factor composition in negative disease factor 2. The distribution of W-values in male and female individuals with ADHD after age and site regression (two-tailed Mann-Whitney U tests, pFDR < 0.05). ADHD, attention-deficit/hyperactivity disorder; FDR, false discovery rates; NF2, negative disease factor 2.
Figure 2. Functional enrichment of gene transcripts related to the negative disease factor 2 of ADHD. A, Two gene lists, including the ADHD risk genes and PLS1+ gene list (related to the 5% z-values and cluster size > 150 voxels), jointly participate in the gene transcription process. B, The expression of overlapped genes between the PLS1+ gene list above and cellular genes, and the enrichment of these overlapped genes in 7 typical cells. ADHD, attention-deficit/hyperactivity disorder; FDR, false discovery rates; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; PLS, the partial least squares; PLS1+, the first positive principal component of PLS regression.
Conclusions:
The atrophy of gray matter volume in the cerebellum posterior lobe may be related to the dysfunction of chemical synaptic transmission within synapses in excitatory and inhibitory neurons, and may further affect the verbal working in NF2 of individuals with ADHD, especially female individuals (Martin, 2024). In the NF1, the gray matter atrophy in brain regions involved in working memory was associated with the abnormal elimination of dendritic spines in post-synapse and affected the function of postsynaptic specialization in inhibitory neurons in NF1 of individuals with ADHD (Martinussen et al., 2005). The increased volume of cerebellum and middle temporal gyrus may be related to motion perception abnormalities caused by distraction in PF2 of individuals with ADHD (Cavanagh, 1992). Our findings provided imaging support for potential phenotypes of ADHD with sexual differences and specifically cellular gene transcription mechanisms.
Disorders of the Nervous System:
Neurodevelopmental/ Early Life (eg. ADHD, autism) 1
Genetics:
Genetics Other
Novel Imaging Acquisition Methods:
Anatomical MRI 2
Keywords:
Attention Deficit Disorder
Modeling
Phenotype-Genotype
Sexual Dimorphism
STRUCTURAL MRI
1|2Indicates the priority used for review
·Figure 1
·Figure 2
Abstract Information
By submitting your proposal, you grant permission for the Organization for Human Brain Mapping (OHBM) to distribute your work in any format, including video, audio print and electronic text through OHBM OnDemand, social media channels, the OHBM website, or other electronic publications and media.
The Open Science Special Interest Group (OSSIG) is introducing a reproducibility challenge for OHBM 2025. This new initiative aims to enhance the reproducibility of scientific results and foster collaborations between labs. Teams will consist of a “source” party and a “reproducing” party, and will be evaluated on the success of their replication, the openness of the source work, and additional deliverables. Click here for more information. Propose your OHBM abstract(s) as source work for future OHBM meetings by selecting one of the following options:
Please indicate below if your study was a "resting state" or "task-activation” study.
Healthy subjects only or patients (note that patient studies may also involve healthy subjects):
Was this research conducted in the United States?
Were any human subjects research approved by the relevant Institutional Review Board or ethics panel? NOTE: Any human subjects studies without IRB approval will be automatically rejected.
Were any animal research approved by the relevant IACUC or other animal research panel? NOTE: Any animal studies without IACUC approval will be automatically rejected.
Please indicate which methods were used in your research:
For human MRI, what field strength scanner do you use?
Provide references using APA citation style.
Chen, H., Uddin, L. Q., Guo, X., Wang, J., Wang, R., Wang, X., . . . Chen, H. (2019). Parsing brain structural heterogeneity in males with autism spectrum disorder reveals distinct clinical subtypes. Human Brain Mapping, 40(2), 628-637.
DSM-5. (2013). Diagnostic and statistical manual of mental disorders: DSM, 5th ed. Arlington, VA, US: American Psychiatric Publishing.
Han, S., Cui, Q., Zheng, R., Li, S., Zhou, B., Fang, K., . . . Zhang, Y. (2023). Parsing altered gray matter morphology of depression using a framework integrating the normative model and non-negative matrix factorization. Nature Communications, 14(1), 4053.
Martin, J. (2024). Why are females less likely to be diagnosed with ADHD in childhood than males? The Lancet Psychiatry, 11(4), 303-310.
Martinussen, R., Hayden, J., Hogg-Johnson, S., & Tannock, R. (2005). A meta-analysis of working memory impairments in children with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 44(4), 377-384.
Rasmussen, E. R., Neuman, R. J., Heath, A. C., Levy, F., Hay, D. A., & Todd, R. D. (2004). Familial clustering of latent class and DSM-IV defined attention-deficit/hyperactivity disorder (ADHD) subtypes. Journal of Child Psychology and Psychiatry, 45(3), 589-598.
Shan, X., Uddin, L. Q., Xiao, J., He, C., Ling, Z., Li, L., . . . Duan, X. (2022). Mapping the heterogeneous brain structural phenotype of autism spectrum disorder using the normative model. Biological Psychiatry, 91(11), 967-976.
Zhang, F., Liu, L., Peng, J., Ding, G., Li, Y., Biswal, B. B., & Wang, P. (2024). Transdiagnostic and diagnosis-specific morphological similarity related transcriptional profile in attention-deficit/hyperactivity disorder and autism spectrum disorder. Journal of the American Academy of Child and Adolescent Psychiatry. in press. doi:10.1016/j.jaac.2024.11.015