GWAS meta-meta-analysis and related analyses revealed a shared genetic background between ADHD and narcolepsy

Abstract

We previously theorized that Attention-Deficit Hyperactivity Disorder (ADHD) may increase susceptibility to narcolepsy and hypersomnia, potentially sharing genomic and pathophysiological features with addictive behaviours linked to Reward Deficiency Syndrome (RDS). We further suggested that the emergence of narcolepsy in individuals with underlying ADHD or RDS may place additional stress on the dopaminergic reward system. To explore this, we conducted comprehensive data mining using GWAS catalog databases focused on ADHD and narcolepsy, identifying three relevant datasets. These were individually analyzed in GWAS meta-analyses, followed by a combined GWAS meta-meta-analysis. From this, we derived a Primary Gene List (PGL) of 512 genes and a Secondary Gene List (SGL) of 42 genes, which were further examined through in-depth silico, systems biology, and pharmacogenomic (PGx) approaches. Our findings revealed a fully connected protein–protein interaction (PPI) network between ADHD and narcolepsy, with FOXP2 and RBFOX1 emerging as shared genes. We also identified schizophrenia as a potential endophenotype linking ADHD and narcolepsy. PGx analysis revealed pharmacogenomic relevance for seven genes from the SGL. To further investigate PGx–PPI relationships, we incorporated ten GARS family genes along with eight identified pharmacogenes in PGx-PPIs, and included FOXP2, RBFOX1, and GRIN2A, despite the absence of PGx data for the latter three. This analysis highlighted DRD2 and NRXN1 as central components of the dopaminergic [Genetic Addiction Risk Severity (GARS)] pathway, forming critical connections in the ADHD–schizophrenia–narcolepsy axis. These results support our initial hypothesis of a shared genetic basis between ADHD and narcolepsy. Additionally, we identified potentially overlapping genes with schizophrenia and highlighted dopaminergic regulatory variants of FOXP2, RBFOX1, and GRIN2A as promising diagnostic markers and therapeutic targets for future research.