Convergence of autism proteins at the cilium.

Unlabelled: Hundreds of high-confidence autism genes have been identified, yet the relevant etiological mechanisms remain unclear. Gene ontology analyses have repeatedly identified enrichment of proteins with annotated functions in gene expression regulation and neuronal communication. However, proteins are often pleiotropic and these annotations are inherently incomplete.

Autism gene variants disrupt enteric neuron migration and cause gastrointestinal dysmotility.

The comorbidity of autism spectrum disorders and severe gastrointestinal symptoms is well-established, yet the molecular underpinnings remain unknown. The identification of high-confidence large-effect autism risk genes offers the opportunity to identify convergent, underlying biology by studying these genes in the context of the gastrointestinal system. Here we show that the expression of these genes is enriched in human prenatal gut neurons as well as their migratory progenitors, suggesting that the development and/or function of these neurons may be disrupted by autism-associated pathogenic variants, leading to gastrointestinal dysfunction.

Five autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes.

Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin.

A foundational atlas of autism protein interactions reveals molecular convergence.

Translating high-confidence (hc) autism spectrum disorder (ASD) genes into viable treatment targets remains elusive. We constructed a foundational protein-protein interaction (PPI) network in HEK293T cells involving 100 hcASD risk genes, revealing over 1,800 PPIs (87% novel). Interactors, expressed in the human brain and enriched for ASD but not schizophrenia genetic risk, converged on protein complexes involved in neurogenesis, tubulin biology, transcriptional regulation, and chromatin modification.

New and emerging approaches to treat psychiatric disorders.

Psychiatric disorders are highly prevalent, often devastating diseases that negatively impact the lives of millions of people worldwide. Although their etiological and diagnostic heterogeneity has long challenged drug discovery, an emerging circuit-based understanding of psychiatric illness is offering an important alternative to the current reliance on trial and error, both in the development and in the clinical application of treatments. Here we review new and emerging treatment approaches, with a particular emphasis on the revolutionary potential of brain-circuit-based interventions for precision psychiatry.

In Search of Biomarkers to Guide Interventions in Autism Spectrum Disorder: A Systematic Review.

Objective: The aim of this study was to catalog and evaluate response biomarkers correlated with autism spectrum disorder (ASD) symptoms to improve clinical trials.

Methods: A systematic review of MEDLINE, Embase, and Scopus was conducted in April 2020. Seven criteria were applied to focus on original research that includes quantifiable response biomarkers measured alongside ASD symptoms.

Genomics, convergent neuroscience and progress in understanding autism spectrum disorder.

More than a hundred genes have been identified that, when disrupted, impart large risk for autism spectrum disorder (ASD). Current knowledge about the encoded proteins - although incomplete - points to a very wide range of developmentally dynamic and diverse biological processes. Moreover, the core symptoms of ASD involve distinctly human characteristics, presenting challenges to interpreting evolutionarily distant model systems.

Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes.

Deleterious genetic variants in POGZ, which encodes the chromatin regulator Pogo Transposable Element with ZNF Domain protein, are strongly associated with autism spectrum disorder (ASD). Although it is a high-confidence ASD risk gene, the neurodevelopmental functions of POGZ remain unclear. Here we reveal the genomic binding of POGZ in the developing forebrain at euchromatic loci and gene regulatory elements (REs).

Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience.

Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD.

Autism Spectrum Disorder Genetics and the Search for Pathological Mechanisms.

Recent progress in the identification of genes and genomic regions contributing to autism spectrum disorder (ASD) has had a broad impact on our understanding of the nature of genetic risk for a range of psychiatric disorders, on our understanding of ASD biology, and on defining the key challenges now facing the field in efforts to translate gene discovery into an actionable understanding of pathology. While these advances have not yet had a transformative impact on clinical practice, there is nonetheless cause for real optimism: reliable lists of risk genes are large and growing rapidly; the identified encoded proteins have already begun to point to a relatively small number of areas of biology, where parallel advances in neuroscience and functional genomics are yielding profound insights; there is strong evidence pointing to mid-fetal prefrontal cortical development as one nexus of vulnerability for some of the largest-effect ASD risk genes; and there are multiple plausible paths forward toward rational therapeutics development that, while admittedly challenging, constitute fundamental departures from what was possible prior to the era of successful gene discovery.

Leveraging large genomic datasets to illuminate the pathobiology of autism spectrum disorders.

"Big data" approaches in the form of large-scale human genomic studies have led to striking advances in autism spectrum disorder (ASD) genetics. Similar to many other psychiatric syndromes, advances in genotyping technology, allowing for inexpensive genome-wide assays, has confirmed the contribution of polygenic inheritance involving common alleles of small effect, a handful of which have now been definitively identified. However, the past decade of gene discovery in ASD has been most notable for the application, in large family-based cohorts, of high-density microarray studies of submicroscopic chromosomal structure as well as high-throughput DNA sequencing-leading to the identification of an increasingly long list of risk regions and genes disrupted by rare, de novo germline mutations of large effect.

A Chromatin Accessibility Atlas of the Developing Human Telencephalon.

To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed temporal, regional, and laminar differences in chromatin accessibility and were correlated with gene expression differences across regions and gestational ages.

The neurodevelopmental disorder risk gene is required for ciliogenesis and control of brain size in embryos.

[dual specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A] is a high-confidence autism risk gene that encodes a conserved kinase. In addition to autism, individuals with putative loss-of-function variants in exhibit microcephaly, intellectual disability, developmental delay and/or congenital anomalies of the kidney and urinary tract. is also located within the critical region for Down syndrome; therefore, understanding the role of in brain development is crucial for understanding the pathobiology of multiple developmental disorders.

Enhancing WNT Signaling Restores Cortical Neuronal Spine Maturation and Synaptogenesis in Tbr1 Mutants.

Tbr1 is a high-confidence autism spectrum disorder (ASD) gene encoding a transcription factor with distinct pre- and postnatal functions. Postnatally, Tbr1 conditional knockout (CKO) mutants and constitutive heterozygotes have immature dendritic spines and reduced synaptic density. Tbr1 regulates expression of several genes that underlie synaptic defects, including a kinesin (Kif1a) and a WNT-signaling ligand (Wnt7b).

Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex.

Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development.

Autism spectrum disorder.

Autism spectrum disorder is a construct used to describe individuals with a specific combination of impairments in social communication and repetitive behaviours, highly restricted interests and/or sensory behaviours beginning early in life. The worldwide prevalence of autism is just under 1%, but estimates are higher in high-income countries. Although gross brain pathology is not characteristic of autism, subtle anatomical and functional differences have been observed in post-mortem, neuroimaging and electrophysiological studies.

Integrative functional genomic analysis of human brain development and neuropsychiatric risks.

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations.

Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder.

Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD.

Lost in Translation: Traversing the Complex Path from Genomics to Therapeutics in Autism Spectrum Disorder.

Recent progress in the genomics of non-syndromic autism spectrum disorder (nsASD) highlights rare, large-effect, germline, heterozygous de novo coding mutations. This distinguishes nsASD from later-onset psychiatric disorders where gene discovery efforts have predominantly yielded common alleles of small effect. These differences point to distinctive opportunities for clarifying the neurobiology of nsASD and developing novel treatments.