Polygenic risk score analysis revealed shared genetic background in attention deficit hyperactivity disorder and narcolepsy

Abstract

Attention deficit hyperactive disorder (ADHD) is a highly heritable neurodevelopmental disorder, and excessive daytime sleepiness is frequently observed in ADHD patients. Excessive daytime sleepiness is also a core symptom of narcolepsy and essential hypersomnia (EHS), which are also heritable conditions. Psychostimulants are effective for the symptomatic control of ADHD (primary recommended intervention) and the two sleep disorders (frequent off-label use). However, the common biological mechanism for these disorders has not been well understood. Using a previously collected genome-wide association study of narcolepsy and EHS, we calculated polygenic risk scores (PRS) for each individual. We investigated a possible genetic association between ADHD and narcolepsy traits in the Hamamatsu Birth Cohort for mothers and children (HBC study) (n = 876). Gene-set enrichment analyses were used to identify common pathways underlying these disorders. Narcolepsy PRS were significantly associated with ADHD traits both in the hyperactivity domain (e.g., P-value threshold < 0.05, β [SE], 5.815 [1.774]; P = 0.002) and inattention domain (e.g., P-value threshold < 0.05, β [SE], 5.734 [1.761]; P = 0.004). However, EHS PRS was not significantly associated with either domain of ADHD traits. Gene-set enrichment analyses revealed that pathways related to dopaminergic signaling, immune systems, iron metabolism, and glial cell function involved in both ADHD and narcolepsy. Findings indicate that ADHD and narcolepsy are genetically related, and there are possible common underlying biological mechanisms for this relationship. Future studies replicating these findings would be warranted to elucidate the genetic vulnerability for daytime sleepiness in individuals with ADHD.

Sleep disturbances in ADHD: investigating the contribution of polygenic liability for ADHD and sleep-related phenotypes

“…This could be due to differences in methodology, given we compared polygenic liability for insomnia in children to their parents' average liability, rather than to screened controls. Our results also contrast with previous PGS studies in children in the general population, which found genetic links between ADHD and sleep phenotypes [9][10][11]. One possibility is that previous results were influenced by the fact that ADHD and sleep problems co-occur in the general population, which was not accounted for.…”

“…with polygenic scores for insomnia [9] and narcolepsy [10]. Additionally, ADHD polygenic scores are associated with sleep disturbances in children in the general population, particularly excessive somnolence and difficulties initiating and maintaining sleep [11].…”

Decoupling sleep and brain size in childhood: An investigation of genetic covariation in the ABCD study

“…Mirroring our null genetic correlations, PRS for brain surface area did not predict childhood insomnia. Instead PRS for ADHD was a significant predictor of both insomnia (at both 9-10-years of age and at the 1-year follow-up) and surface area in the frontal cortex and insula, which is consistent with recent studies showing genetic associations between ADHD, narcolepsy, 48 and sleep disturbances more broadly. 49 Our findings of positive genetic correlations between childhood sleep disturbance and ADHD are also in agreement with previous research documenting behavioral comorbidity 50,51 and overlapping affected neural systems.…”

Clinical Utility of Polygenic Risk Score in Sleep Disorder

“…Another PRS study has suggested that narcolepsy is genetically associated with attention-deficit/hyperactivity disorder (ADHD) [18]. The discovery sample for narcolepsy consisted of 1,562 normal controls and 409 patients with narcolepsy.…”