Pre-treatment clinical behavioral and blood leukocyte gene expression patterns predict rate of change in response to early intervention in autism

Published on Dec 22, 2020in medRxiv
· DOI :10.1101/2020.12.21.20248674
Michael V. Lombardo56
Estimated H-index: 56
(IIT: Istituto Italiano di Tecnologia),
Elena Maria Busuoli (IIT: Istituto Italiano di Tecnologia)+ 11 AuthorsKaren Pierce51
Estimated H-index: 51
(UCSD: University of California, San Diego)
Sources
Abstract
Early detection and intervention are believed to be key to facilitating better outcomes in children with autism, yet the impact of age at treatment start on outcome is poorly understood. While clinical traits such as language ability have been shown to predict treatment outcome, whether or not and how information at the genomic level can predict treatment outcome is unknown. Leveraging a cohort of toddlers with autism who all received the same standardized intervention at a very young age and provided a blood sample, here we find that very early treatment engagement (i.e., < 24 months) leads to greater gains while controlling for time in treatment. Pre-treatment clinical behavioral measures predicts 21% of the variance in the rate of skill growth during early intervention. Pre-treatment blood leukocyte gene expression patterns also predicts rate of skill growth, accounting for 13% of the variance treatment slopes. Results indicated that 295 genes can be prioritized as driving this effect. These treatment-relevant genes highly interact at the protein level, are enriched for differentially histone acetylated genes in autism post-mortem cortical tissue, and are normatively highly expressed in variety of subcortical and cortical areas important for social-communication and language development. This work indicates for the first time that gene expression can predict the rate of early intervention response and that a key biological factor linked to treatment outcome could be the susceptibility for epigenetic change via mechanisms such as histone acetylation.
References80
Newest
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#2Lisa T. Eyler (UCSD: University of California, San Diego)H-Index: 47
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Cortical regionalization develops via genomic patterning along anterior-posterior (A-P) and dorsal-ventral (D-V) gradients. Here we find that normative A-P and D-V genomic patterning of cortical surface area (SA) and thickness (CT) present in typically developing and autistic toddlers with good early language outcome, is absent in autistic toddlers with poor early language outcome. Autistic toddlers with poor early language outcome are instead specifically characterized by secondary and independ...
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#1Michael V. Lombardo (IIT: Istituto Italiano di Tecnologia)H-Index: 56
#2Lisa T. Eyler (UCSD: University of California, San Diego)H-Index: 47
Last. Eric Courchesne (UCSD: University of California, San Diego)H-Index: 116
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#1Stavros Trakoshis (IIT: Istituto Italiano di Tecnologia)H-Index: 2
#2Pablo Martínez-Cañada (IIT: Istituto Italiano di Tecnologia)H-Index: 6
Last. Alessandro Gozzi (IIT: Istituto Italiano di Tecnologia)H-Index: 38
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Autism is a condition that is usually diagnosed early in life that affects how a person communicates and socializes, and is often characterized by repetitive behaviors. One key theory of autism is that it reflects an imbalance in levels of excitation and inhibition in the brain. Excitatory signals are those that make other brain cells more likely to become active; inhibitory signals have the opposite effect. In non-autistic individuals, inhibitory activity outweighs excitatory activity. In peopl...
17 CitationsSource
#1Vahid H. Gazestani (University of California, Berkeley)H-Index: 1
#2Austin W. T. Chiang (University of California, Berkeley)H-Index: 8
Last. Nathan E. Lewis (University of California, Berkeley)H-Index: 44
view all 4 authors...
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#1Eric Courchesne (UCSD: University of California, San Diego)H-Index: 116
#2Vahid H. Gazestani (UCSD: University of California, San Diego)H-Index: 10
Last. Nathan E. Lewis (UCSD: University of California, San Diego)H-Index: 44
view all 3 authors...
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view all 5 authors...
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#1Matthew J. Maenner (CDC: Centers for Disease Control and Prevention)H-Index: 29
#2Kelly A Shaw (CDC: Centers for Disease Control and Prevention)H-Index: 20
Last. Patricia M. Dietz (CDC: Centers for Disease Control and Prevention)H-Index: 56
view all 34 authors...
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140 CitationsSource
#1F. Kyle Satterstrom (Broad Institute)H-Index: 25
#2Jack A. KosmickiH-Index: 25
Last. Mark J. DalyH-Index: 213
view all 190 authors...
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#1Michael V. Lombardo (University of Cambridge)H-Index: 56
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Hundreds of genes are implicated in autism spectrum disorder (ASD), but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here we analyzed leukocyte transcriptomics from 1- to 4-year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes highly expressed genes during fetal brain development. This network is dysregulated in human induced pluripotent stem cell-derived neuron models of ASD...
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