Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells

Human Genomics

Bisan Samara¹  Nasna Nassir²  Seyed Ali Safizadeh Shabestari²  Abdulrahman Ali²  Awab Ahmed²  Ibrahim M. Inuwa²  Asma Bankapur²  Bakhrom K. Berdiev²  Mohammed Uddin³  Ammar AlBanna⁴  Marc Woodbury-Smith⁵  Mehdi Zarrei⁶  Jennifer L. Howe⁶  Stephen W. Scherer⁷ 

[1] Biomedical Engineering Department, McGill University, Montréal, QC, Canada;College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE;College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE;Cellular Intelligence (Ci) Lab, GenomeArc Inc., Toronto, ON, Canada;Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE;The Mental Health Center of Excellence, Al Jalila Children’s Speciality Hospital, Dubai, UAE;The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON, Canada;Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK;The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON, Canada;Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada;The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON, Canada;Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada;Molecular Genetics, University of Toronto, Toronto, ON, Canada;

关键词: Single-cell transcriptomics;    Autism spectrum disorder;    De novo LOF variant;    Glial cell type;    Brain tissue;   

DOI  :  10.1186/s40246-021-00368-7

来源: Springer

【 摘 要 】

BackgroundIn recent years, several hundred autism spectrum disorder (ASD) implicated genes have been discovered impacting a wide range of molecular pathways. However, the molecular underpinning of ASD, particularly from the point of view of ‘brain to behaviour’ pathogenic mechanisms, remains largely unknown.MethodsWe undertook a study to investigate patterns of spatiotemporal and cell type expression of ASD-implicated genes by integrating large-scale brain single-cell transcriptomes (> million cells) and de novo loss-of-function (LOF) ASD variants (impacting 852 genes from 40,122 cases).ResultsWe identified multiple single-cell clusters from three distinct developmental human brain regions (anterior cingulate cortex, middle temporal gyrus and primary visual cortex) that evidenced high evolutionary constraint through enrichment for brain critical exons and high pLI genes. These clusters also showed significant enrichment with ASD loss-of-function variant genes (p < 5.23 × 10–11) that are transcriptionally highly active in prenatal brain regions (visual cortex and dorsolateral prefrontal cortex). Mapping ASD de novo LOF variant genes into large-scale human and mouse brain single-cell transcriptome analysis demonstrate enrichment of such genes into neuronal subtypes and are also enriched for subtype of non-neuronal glial cell types (astrocyte, p < 6.40 × 10–11, oligodendrocyte, p < 1.31 × 10–09).ConclusionAmong the ASD genes enriched with pathogenic de novo LOF variants (i.e. KANK1, PLXNB1), a subgroup has restricted transcriptional regulation in non-neuronal cell types that are evolutionarily conserved. This association strongly suggests the involvement of subtype of non-neuronal glial cells in the pathogenesis of ASD and the need to explore other biological pathways for this disorder.

【 授权许可】

CC BY