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SUMMARY:Broad Transcriptomic Dysregulation  Occurs Across the Cortex in AS
 D - Prof. Michael Gandal\, UPenn
DTSTART:20230518T140000Z
DTEND:20230518T150000Z
UID:TALK199669@talks.cam.ac.uk
CONTACT:Sofia Orellana
DESCRIPTION:Neuropsychiatric disorders classically lack defining brain pat
 hologies\, but recent work has demonstrated dysregulation at the molecular
  level\, characterized by transcriptomic and epigenetic alterations. In au
 tism spectrum disorder (ASD)\, this molecular pathology involves the upreg
 ulation of microglial\, astrocyte and neural-immune genes\, the downregula
 tion of synaptic genes\, and attenuation of gene-expression gradients in c
 ortex. However\, whether these changes are limited to cortical association
  regions or are more widespread remains unknown. To address this issue\, w
 e performed RNA-sequencing analysis of 725 brain samples spanning 11 corti
 cal areas from 112 post-mortem samples from individuals with ASD and neuro
 typical controls. We find widespread transcriptomic changes across the cor
 tex in ASD\, exhibiting an anterior-to-posterior gradient\, with the great
 est differences in primary visual cortex\, coincident with an attenuation 
 of the typical transcriptomic differences between cortical regions. Single
 -nucleus RNA-sequencing and methylation profiling demonstrate that this ro
 bust molecular signature reflects changes in cell-type-specific gene expre
 ssion\, particularly affecting excitatory neurons and glia. Both rare and 
 common ASD-associated genetic variation converge within a downregulated co
 -expression module involving synaptic signalling\, and common variation al
 one is enriched within a module of upregulated protein chaperone genes. Th
 ese results highlight widespread molecular changes across the cerebral cor
 tex in ASD\, extending beyond association cortex to broadly involve primar
 y sensory regions.
LOCATION:Online
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