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.
Highlights
Attention deficit hyperactive disorder (ADHD) is a common neurodevelopmental disorder with onset occurring in childhood
Capitalizing on the much higher prevalence of narcolepsy in the Japanese population (0.16–0.18%)[14] compared to the Caucasian population (0.02–0.06%)[15], and using the previous Japanese genome-wide association studies (GWAS) study of narcolepsy as a discovery cohort, we investigated a possible genetic association between ADHD traits and narcolepsy in our birth cohort sample from the HBC study
The narcolepsy polygenic risk scores (PRS) was significantly associated with ADHD traits at various P-value thresholds either in the hyperactivity (e.g., P-value threshold < 0.05, β [SE], 5.815 [1.774]; P = 0.002), inattentive domains (e.g., P-value threshold < 0.05, β [SE], 5.734 [1.761]; P = 0.004) and total score (e.g., P-value threshold < 0.05, β [SE], 6.496 [1.676]; P = 0.001) (Table 2, Fig. 1a, b, Supplemental figure)
Summary
Attention deficit hyperactive disorder (ADHD) is a common neurodevelopmental disorder with onset occurring in childhood. Genetic factors play an important role in the development of ADHD, with a heritability of Recently, based on a polygenic model for complex disorders, polygenic risk scores (PRS) have been calculated and widely used to explain the genetic liability of individuals for certain diseases or phenotypes, using common genetic variants tested in GWAS3. PRS can be used to examine the genetic association between two different. The association of ADHD PRS has been reported with depressive symptoms[4], body mass index[5], substance use disorder[6], and educational attainment[7], but no examination has far been conducted with sleep disorders. ADHD frequently show excessive daytime sleepiness (EDS)[8]. The prevalence of ADHD in individuals with narcolepsy is (~35%)[9] higher than in the general population (~5%)[10]
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