Shared genetic architecture and causal pathways between attention deficit hyperactivity disorder and restless legs syndrome

Previous studies have revealed a significant overlap between ADHD and RLS populations, with shared pathological mechanisms such as dopaminergic function and iron metabolism deficits. However, the genetic mechanisms underlying these connections remain unclear. In our study, we conducted a genome-wide genetic correlation analysis to confirm a shared genetic structure between ADHD and RLS. We identified five pleiotropic loci through PLACO analysis, with colocalization analysis revealing a shared causal genetic variant, rs12336113, located in an intron of the PTPRD gene within one of these loci. Additionally, we identified 14 potential shared genes and biological pathways between these diseases. Protein-protein interaction analysis demonstrated close interactions among six genes: PTPRD, MEIS1, MAP2K5, SKOR1, BTBD9, and TOX3. We further investigated gene-driven causal pathways using univariable Mendelian randomization (MR), multivariable MR, and Network MR analyses. Our findings indicate that ADHD may indirectly promote the onset of RLS by advancing the age of first birth, while RLS could indirectly contribute to ADHD by reducing fractional anisotropy in body of corpus callosum. Notably, an increase in radial diffusivity, rather than a decrease in axial diffusivity, played a crucial role in this process. In conclusion, our research supports a close genetic link between ADHD and RLS, identifying PTPRD as the most likely pleiotropic gene between these conditions. Moreover, ADHD may indirectly promote RLS onset by advancing the age of first birth, while RLS may indirectly promote ADHD onset by causing demyelination in body of corpus callosum. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### 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: The GWAS data used in this study were obtained from the following websites: Psychiatric Genomics Consortium: https://pgc.unc.edu/for-researchers/download-results/ Decode Consortium: https://www.decode.com/summarydata/ Brain Imaging Genetics Knowledge Portal: https://bigkp.org/ IEU Open GWAS Project: https://gwas.mrcieu.ac.uk/ GWAS Catalog: https://www.ebi.ac.uk/gwas/ For specific data sources, please refer to Table S1 in the text. 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 All data produced in the present study are available upon reasonable request to the authors.