PTPRD pleiotropy, genetically driven childbirth timing, and corpus callosum microstructure as potential mechanisms...

To investigate the genetic mechanisms underlying the comorbidity of attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS).

We conducted a three-stage study to investigate the genetic relationship between ADHD and RLS. In the first stage, we used linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) to assess genome-wide genetic correlations. In the second stage, pleiotropic analysis under composite null hypothesis (PLACO) and functional mapping and annotation (FUMA) were applied to identify pleiotropic genes shared by both disorders. In the third stage, network Mendelian randomization (MR) was used to explore gene-driven causal pathways between ADHD and RLS.

Genome-wide analyses revealed a significant genetic correlation between ADHD and RLS. Fourteen potential pleiotropic genes were identified, six of which showed strong protein-protein interaction evidence. Colocalization analysis confirmed PTPRD as a likely causative gene. Pleiotropic loci were enriched in brain tissue, and functional annotation indicated involvement in pathways related to learning, memory, synaptic plasticity, and neural development. MR analysis demonstrated bidirectional gene-driven causality: ADHD may increase the risk of RLS by leading to an earlier age at first childbirth, whereas RLS may contribute to ADHD via reduced fractional anisotropy in the corpus callosum body, primarily driven by increased radial diffusivity.

Our findings suggest that the PTPRD gene may contribute to the comorbidity of ADHD and RLS through pleiotropic effects. Genetically influenced childbirth timing and alterations in corpus callosum white matter microstructure may represent potential neurodevelopmental pathways linking the two conditions.