The genetic relationship between ADHD and shortened telomeres points to neurodevelopmental mechanisms.

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is often accompanied by other psychiatric and somatic conditions. Telomere shortening as an accelerated biological aging marker may underlie this aggregate burden. Telomere length (TL) has previously been associated with childhood inattention and hyperactivity, as well as other neuropsychiatric conditions. We hypothesize that TL and ADHD may share overlapping genetic influences, suggesting that some of the same genes could affect both cellular aging and ADHD traits. We investigated the pleiotropic and causal associations between these traits. Using the latest and largest publicly available genome-wide association study (GWAS) summary data for ADHD (38,691 cases and 186,843 controls) and TL (472,174 subjects), we tested causality, global and local genetic correlations, and joint genomic effects. Polygenic scores (PGS) were evaluated in an independent clinical sample of 665 ADHD cases and 995 controls, and TL was quantified via qPCR in a subsample of 370 subjects. The pleiotropy analysis showed global and local (a chromosome 17 locus) negative correlations. Shared genomic analysis showed loci enriched across several chromosomes, notably including the same chromosome 17 locus. This locus contains a diverse set of genes involved in many biological pathways impacting core cellular functions, tissue development, cell cycle, and apoptosis. Mendelian randomization indicated a unidirectional causal effect of ADHD on shorter TL across four methods. In our independent clinical sample, TL was shorter in individuals with ADHD. Lastly, higher PGS for longer TL was associated with reduced ADHD symptomatology. Our findings suggest that ADHD may contribute to TL, and genetic predisposition to shorter TL is associated with greater ADHD severity.