Functional gradient perturbation in Wilson disease correlates with structural lesions and transcriptomic specializations

Functional dysregulations in multiple regions are caused by excessive copper deposition in the brain for Wilson disease (WD). While the biological mechanism of these dysregulations was thought to be the absent or reduced expression of the ATP7B protein in the liver, mechanisms for such gene impacting brain function remain unexplored. Here, we used a large cohort of resting-state fMRI data (105 WD patients and 93 healthy controls) to derive the functional connectome gradient, and its WD-related alterations were further evaluated. Then, we used Neurosynth, clinical data, and whole-brain gene expression to examine the meta-analytic cognitive function, clinical phenotypes, and transcriptional specializations related to WD gradient alterations. In parallel, spatial correlation between gradient and gray matter volume was accessed for both WD patients and healthy controls. Compared to controls, WD patients exhibited principal gradient alterations in both global and system levels and regional alterations mainly distributed in the sensorimotor, visual, ventral attention, subcortical, and default mode networks. Meta-analytic terms and clinical characters showed the correlations of these gradient alterations in motor-related processing, higher-order cognition, neurological symptom, and age. Results of spatial correlation revealed structure-function decoupling in multiple networks, especially in subcortical and visual networks. Within the cortex, the gradient alterations derived transcriptional specializations of WD that mainly display properties indicative of ion homeostasis, neural development, and motor controls. Within the subcortical regions, we for the first time characterized the role of the ATP7B gene impacting subcortical function. Transcriptional specializations of WD within both cortex and subcortical regions were also associated with neurological and psychiatric disorders, explaining the mechanism underlying complex clinical symptoms from the biological level for WD. In addition, we further illustrated that structural lesion and gradient perturbation shared similar transcriptional specializations in both cortex and subcortical regions for WD. These findings bridged functional gradient perturbation to structural lesions and transcriptional profiles in WD, possibly promoting our understanding of the neurobiological underpinnings underlying the emergence of complex neurological and psychiatric phenotypes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Natural Science Foundation of China (81973825 and U22A20366), the University Synergy Innovation Program of Anhui Province (GXXT-2020-025), the Project BEBPC-TCM (2019XZZX-NB001), the Natural Science Research Project of Anhui Universities (KJ2021A0580 and KJ2021A0555), the Natural Science Foundation of Anhui Province (2108085QH367) and the Open Fund Project of Key Laboratory of Xin'an Medicine of Ministry of Education (2020xayx12). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the First Affiliated Hospital of Anhui University of Chinese Medicine gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymised data are available on request to the corresponding author. Gene expression data that was used for transcriptional analysis can be found in the ABHA database ().