Variations in Genes Related to Sleep Patterns in Children With Autism Spectrum Disorder

Abstract

Background: Sleep disturbance is a frequent comorbidity in children with autism spectrum disorder (ASD), affecting an estimated 40–80% of cases. Previous reports have shown relationships between several circadian rhythm–related genes and sleep problems in ASD. The purpose of the present study was to relate variation in and around melatonin synthesis and suprachiasmatic nucleus genes to sleep problems in a large sample of children with ASD. Method: This secondary analysis used existing genotypic and phenotypic data for 2,065 children, aged 4–18 years, from the Simons Simplex Collection (SSC). Sleep problems were measured with the SSC Sleep Interview. Expression quantitative trait loci and single nucleotide polymorphisms in 25 circadian genes were chosen primarily for their impact on expression levels of target genes in the brain. Associations between variants and composite sleep problems, nighttime problems, daytime problems, and sleep duration problems were calculated using logistic regression analysis. Age, sex, nonverbal IQ, ASD severity, gastrointestinal distress, seizures, and ancestry were included as covariates. Transmission disequilibrium tests were performed to test for overtransmission of alleles in the same variants. Results: No significant associations or transmission disequilibrium were found between gene variants and sleep problems in this sample of children with ASD. Conclusion: Variation in expression of investigated genes in the melatonin synthesis and suprachiasmatic nucleus pathways did not have notable impacts on sleep problems in this large sample of children with ASD. Future research could explore translational and posttranslational effects of these genes or the effects of genes in other sleep-homeostasis pathways on sleep patterns.

Sleep Problems in Children with ASD and Gene Disrupting Mutations

“…Large scale genomic studies have identified genes tied directly to circadian rhythm pathways (review provided by Veatch, Keenan, Gehrman, Malow, & Pack, 2017) and enrichment of disruptions to specific melatonin pathway genes have been identified amongst autistic individuals with sleep onset difficulties (Veatch, Maxwell-Horn, & Malow, 2015). Despite these associations, recent work did not find a connection between dnLGDs known to impact circadian rhythms (e.g., ASMT, CLOCK, MTNR1B, TIMELESS) and parent-reported sleep problems (Johansson, Dorman, Chasens, Feeley, & Devlin, 2019). Considering the additional biological mechanisms implicated by other non-circadian rhythm genes (see Iossifov et al, 2014), exploring the differences in sleep problem presentation by dnLGD mutation subgroups of ASD may shed light on the phenotypic variability we see in co occurring sleep conditions and illuminate the specific neurobiological mechanisms that are disrupting sleep in autistic individuals.…”

Investigating the contributions of circadian pathway and insomnia risk genes to autism and sleep disturbances

“…The link between ASD and circadian pathways has been investigated in a few studies, however, the potential relationship remains unclear. Studies, mainly focusing on clock genes, were not able to associate common variants in circadian genes with ASD or sleep disturbances in this population [20][21][22][23]. As an example, a 2019 study showed SNPs within 25 clock and melatonin genes were not associated with broad night and daytime sleep issues in 2065 ASD youth in the Simon Simplex Collection [22].…”

“…Studies, mainly focusing on clock genes, were not able to associate common variants in circadian genes with ASD or sleep disturbances in this population [20][21][22][23]. As an example, a 2019 study showed SNPs within 25 clock and melatonin genes were not associated with broad night and daytime sleep issues in 2065 ASD youth in the Simon Simplex Collection [22]. The relationship between the circadian system and ASD has also been investigated through melatonin regulation.…”

Chronic Fluoride Exposure and the Risk of Autism Spectrum Disorder

“…The recent data for 2065 ASD children aged 4–18 years with sleep disturbance were analyzed to investigate the variation in genes around melatonin synthesis [49]. No significant associations were found between 25 circadian gene variants and sleep problems in this sample of children with ASD.…”