Atypical genomic cortical patterning in autism with poor early language outcome

Lombardo, Michael; Eyler, Lisa T.; Pramparo, Tiziano; Gazestani, Vahid H.; Hagler, Donald J.; Chen, Chi‐Hua; Dale, Anders M.; Seidlitz, Jakob; Bethlehem, Richard A. I.; Bertelsen, Natasha; Barnes, Cynthia Carter; Lopez, Linda; Campbell, Kathleen; Lewis, Nathan E.; Pierce, Karen; Courchesne, Eric

doi:10.1126/sciadv.abh1663

Cited by 36 publications

(57 citation statements)

References 85 publications

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“…Furthermore, heritability analyses suggest a genetic basis to the organization of cortical surface area and thickness along principal anterior-posterior and dorsal-ventral aspects, respectively (Chen et al, 2012(Chen et al, , 2013Valk et al, 2020). Follow up work has suggested that these genetically imposed patterns are disrupted in developmental disorders (Ball et al, 2020;Lombardo et al, 2021). More recent complementary work has provided evidence for an isolated directional gradient of gene expression in the adult brain, relating this gradient to other brain (neurodegenerative) diseases (Vogel et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Conserved whole-brain spatiomolecular gradients shape adult brain functional organization

Vogel

Alexander-Bloch

Wagstyl

et al. 2022

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Cortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, how these gradients relate to adult brain function, and whether they are maintained in the adult brain, remains unknown. Here we uncover three axes of topographic variation in gene expression in the adult human brain that specifically capture previously identified rostral-caudal, dorsal-ventral and medial-lateral axes of early developmental patterning. The interaction of these spatiomolecular gradients i) accurately predicts the location of unseen brain tissue samples, ii) delineates known functional territories, and iii) explains the topographical variation of diverse cortical features. The spatiomolecular gradients are distinct from canonical cortical functional hierarchies differentiating primary sensory cortex from association cortex, but radiate in parallel with the axes traversed by local field potentials along the cortex. We replicate all three molecular gradients in three independent human datasets as well as two non-human primate datasets, and find that each gradient shows a distinct developmental trajectory across the lifespan. The gradients are composed of several well known morphogens (e.g., PAX6 and SIX3), and a small set of genes shared across gradients are strongly enriched for multiple diseases. Together, these results provide insight into the developmental sculpting of functionally distinct brain regions, governed by three robust transcriptomic axes embedded within brain parenchyma.

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Section: Introductionmentioning

confidence: 99%

Conserved whole-brain spatiomolecular gradients shape adult brain functional organization

Vogel

Alexander-Bloch

Wagstyl

et al. 2022

Preprint

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“…While the brain is largely an inaccessible tissue to assay mechanisms like gene expression in living patients, blood leukocyte gene expression has revealed a number of interesting brain-relevant characteristics that can be related to different phenotypes in living patients. Leukocyte expression patterns can be used in a classifier to predict diagnostic status [ 24 ], correlate with total brain size [ 25 ], and are related to large-scale functional neural systems response to speech [ 26 ], the patterning of thickness and surface area in the cerebral cortex [ 27 ], and social symptom severity [ 28 ]. Differentially expressed genes in blood leukocytes are part of extended gene networks that are linked to highly penetrant ASD-related mutations [ 28 ].…”

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confidence: 99%

Pre-treatment clinical and gene expression patterns predict developmental change in early intervention in autism

et al. 2021

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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 the 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 predict 21% of the variance in the rate of skill growth during early intervention. Pre-treatment blood leukocyte gene expression patterns also predict the rate of skill growth, accounting for 13% of the variance in 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 postmortem cortical tissue, and are normatively highly expressed in a variety of subcortical and cortical areas important for social communication and language development. This work suggests that pre-treatment biological and clinical behavioral characteristics are important for predicting developmental change in the context of early intervention and that individualized pre-treatment biology related to histone acetylation may be key.

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“…In line with this, it has been shown that DHT increases proliferation of intermediate progenitors and basal radial glia (79). Also, differences in proliferative processes through symmetric cell division in IP and RG lead to atypical cortical expansion of surface area in autism (80–82). These downstream consequence of DHT may impact excitatory neuronal signaling, due to expansion of surface area via increased number of cortical columns and neurons within each column.…”

Section: Discussionmentioning

confidence: 99%

The link between autism and sex-specific neuroanatomy, and associated cognition and gene expression

Floris

Peng

Warrier

et al. 2022

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Objectives. The male preponderance in autism spectrum conditions (ASC) prevalence is among the most pronounced sex ratios across different neurodevelopmental conditions. Here, we aimed to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression. Methods. Using a novel deep learning framework trained to predict biological sex, we compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale datasets were employed at different stages of the analysis pipeline: a) Pre-training: the UK Biobank sample (>10.000 individuals); b) Transfer learning and validation: the ABIDE datasets (1,412 individuals, 5-56 years of age); c) Test and discovery: the EU-AIMS/AIMS-2-TRIALS LEAP dataset (681 individuals, 6-30 years of age) and d) Specificity: the Neuroimage and ADHD200 datasets (887 individuals, 7-26 years of age). Results: Across both ABIDE and LEAP we showed that features positively predictive of neurotypical males were on average more predictive of autistic males (P=1.1e-23). Features positively predictive of neurotypical females were on average less predictive of autistic females (P=1.2e-22). These accuracy differences in autism were not observed in individuals with ADHD. In autistic females the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also with associated gene expression patterns of midgestational cell types. Conclusions: Our results demonstrate a shift in both autistic male and female individuals' neuroanatomy towards male-characteristic patterns associated with typically sex-differential, social cognitive features and related gene expression patterns. Findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.

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Atypical genomic cortical patterning in autism with poor early language outcome

Cited by 36 publications

References 85 publications

Conserved whole-brain spatiomolecular gradients shape adult brain functional organization

Conserved whole-brain spatiomolecular gradients shape adult brain functional organization

Pre-treatment clinical and gene expression patterns predict developmental change in early intervention in autism

The link between autism and sex-specific neuroanatomy, and associated cognition and gene expression

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