A Gene First Approach to Understanding Sleep Problems in Autism

Poster Presentation
Friday, May 3, 2019: 11:30 AM-1:30 PM
Room: 710 (Palais des congres de Montreal)
R. Tesfaye1, G. Huguet2, Z. Schmilovich3, O. Diallo4, A. Dionne-Laporte5, A. Yusuf6, B. Chaumette3, M. Elsabbagh7, G. A. Rouleau1 and S. Jacquemont8, (1)Neurology and Neurosurgery, McGill University, Montreal, QC, Canada, (2)Research Center of UHC Sainte-Justine, Montreal, QC, Canada, (3)Human Genetics, McGill University, Montreal, QC, Canada, (4)MNI Brain Tumour Research Center, McGill University, Montreal Neurological Institute, Montreal, QC, Canada, (5)MNI Brain Tumour Research Center, McGill University, Montreal, QC, Canada, (6)Psychiatry, McGill University, Montreal, QC, Canada, (7)McGill University, Montreal, PQ, Canada, (8)CHU Sainte Justine, University of Montreal, Montreal, QC, Canada
Background: Sleep is disturbed in up to 80% of youth with autism spectrum disorder (ASD). It’s suggested that these sleep problems may be attributed to genetic abnormalities. It is well established that the circadian rhythm is regulated by a network of core circadian clock genes expressed in the suprachiasmatic nucleus. However, the genetic contribution to the two most prevalent sleep complaints in ASD, namely insomnia and sleep duration abnormality, remains unknown. A recent genome wide association studies (GWAS) including over one million adults, implicated 959 candidate genes with insomnia symptomatology, 203 for poor sleep duration, and other risk genes for various sleep traits. New GWAS findings, in addition to established circadian genes, may provide a gene-first approach to bridge the current knowledge gap in understanding the neurobiological underpinnings of sleep disturbance in ASD.

Objectives: Our goal was to determine whether differences in genetic variants within a) core circadian clock genes b) circadian pathway genes and c) sleep trait candidate genes, are observed between individuals with ASD and their unaffected siblings. We expect significantly more copy number variants (CNVs) encompassing sleep in individuals with ASD in comparison to siblings without a diagnosis.

Methods: We used available data from the Simons Simplex Collection (SSC), a comprehensive phenotyped and genotyped sample of more than 2,583 individuals with ASD (4 -18 years) and their families (parents and non-diagnosed sibling). A list of circadian clock genes were identified in existing literature, pathway genes were extracted from published databases (KEEGPathway and GeneOntology) and GWAS sleep trait candidate genes were taken from Jansen et al, 2018. Microarray technology was used to identify CNVs, pipeline detections from our previous publications were applied to call relevant CNVs. We first investigated the risk of ASD by comparing diagnosed youth to siblings who were carriers or not of rare CNVs (< 0.1%), using the sleep genes identified.

Results: After a microarray quality control, 2091 pairs of ASD youth and siblings remained. When CNVs were filtered by all genes present in our different sleep lists, we found 5% of ASD youth with a rare deletion compared to 3.1% of siblings, while 7.9% of youth with ASD had a rare duplication compared to 6.4% of siblings. A Fisher’s exact test revealed a significant excess of deletions encompassing sleep genes in individuals with ASD compared to unaffected siblings (p=0.003; Odds ratio 1.6; CI95% [1.2 ; 2.3]).

Conclusions:This is the first study to examine CNVs related to sleep in ASD. Our findings demonstrate that variations within sleep-related genes are more frequent in youth with ASD compared to sibling controls. This suggests that sleep disturbance may be inherently linked to the biological etiology of ASD. Future investigations between genetic variants of sleep, brain connectivity and behavioural/cognitive phenotypes will be conducted on a subset of this ASD population.

See more of: Behavioral Genetics
See more of: Behavioral Genetics