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

Area of Science:

• Neurogenetics
• Psychiatric disorders
• Complex trait genetics

Background:

• Attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS) are frequently comorbid, suggesting shared underlying biological mechanisms.
• Understanding the genetic overlap between ADHD and RLS is crucial for elucidating their shared pathophysiology and developing targeted interventions.

Purpose of the Study:

• To investigate the genome-wide genetic correlation and shared pleiotropic genes between ADHD and RLS.
• To explore potential gene-driven causal pathways linking ADHD and RLS using network Mendelian randomization.

Main Methods:

• Genome-wide genetic correlation analysis using LDSC and HDL.
• Identification of pleiotropic genes using PLACO and FUMA.
• Network Mendelian randomization to infer causal relationships.

Main Results:

• Significant genome-wide genetic correlation between ADHD and RLS.
• Identification of 14 pleiotropic genes, with PTPRD confirmed as a likely causative gene.
• Bidirectional causality: ADHD influencing RLS via childbirth timing and RLS affecting ADHD via corpus callosum microstructure alterations.

Conclusions:

• The PTPRD gene plays a role in the comorbidity of ADHD and RLS through pleiotropic effects.
• Genetically influenced childbirth timing and corpus callosum white matter alterations are potential neurodevelopmental pathways linking ADHD and RLS.