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.