GABAergic Circuits as Common Pathways Disrupted in the Genetic Basis of Sleep Phenotypes and Rare Neurodevelopmental Disorders

Keywords

sleep - neurodevelopment - GABA - genetic risk

Introduction: Sleep-related phenotypes have been frequently reported in neurodevelopmental disorders (NDD), with special emphasis in autism spectrum disorder (ASD), yet the convergent pathogenetic mechanisms between these comorbidities are largely unknown. Recent efforts on large genomic datasets have shown shared genetic risk that link psychiatric and sleep traits; however, the neuronal circuits affected by these genetic variants remain to be discovered.

Aim: We performed a gene enrichment study that (1) identified risk genes that contribute to both NDD/ASD and sleep phenotypes and (2) determined cellular and molecular pathways enriched among these shared genes.

Methods: We manually curated two sets of genes, one associated to neurodevelopmental phenotypes and the other to sleep phenotypes (e.g., insomnia, narcolepsy, sleep duration, chronotype, among others). The later gene list was heavily driven by hits in genome-wide association studies, while the first gene list was based on genes that reached genome-wide significancy in the two largest NDD/ASD exome studies performed to date. Using Fisher's exact test and considering a total 21,196 genes in the human genome, we tested the statistical significancy of the overlap between these two gene lists and generated a third gene list containing their intersection. Benjamini-Hochberg test, adjusting for multiple comparisons, was used to identify enriched Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms that were over-represented among the intersect gene list.

Results: There were 41 overlapping genes between the gene list associated to sleep phenotypes (1,064 genes total) and the gene list associated to NDD (307 genes total), indicating significantly more overlap than expected by chance (p value = 1.1e-8, OR = 3.0). Among the top significantly enriched terms on these 41 intersect genes are GABAergic synapse (p value = 0.004, OR = 25.3, KEEG), GABA receptor complex (p value = 0.004, OR = 60.1, GO:1902711), GABA-gated chloride ion channel activity (p value = 0.005, OR = 93.0, GO:0022851), and GABAergic receptor activity (p value = 0.008, OR = 51.1, GO: 0016917).

Conclusions: An over-representation analysis identified several enriched pathways that suggest GABAergic circuits as potential shared mechanisms between sleep phenotypes and NDD. This overlapping gene set and the highlighted biological pathways may serve as a preliminary stepping-stone for new functional investigations of sleep and NDD/ASD shared genetic mechanisms.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
15 June 2023