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Autism spectrum disorder is typical of the majority of neuropsychiatric syndromes in that it is defined by signs and symptoms, rather than by aetiology. Not surprisingly, the causes of this complex human condition are manifold and include a substantial genetic component. Recent developments in gene-hunting technologies and methods, and the resulting plethora of genetic findings, promise to open new avenues to understanding of disease pathophysiology and to contribute to improved clinical management. Despite remarkable genetic heterogeneity, evidence is emerging for converging pathophysiology in autism spectrum disorder, but how this notion of convergent pathways will translate into therapeutics remains to be established. Leveraging genetic findings through advances in model systems and integrative genomic approaches could lead to the development of new classes of therapies and a personalised approach to treatment.

Large-scale genomic investigations have just begun to illuminate the molecular genetic contributions to major psychiatric illnesses, ranging from small-effect-size common variants to larger-effect-size rare mutations. The findings provide causal anchors from which to understand their neurobiological basis. Although these studies represent enormous success, they highlight major challenges reflected in the heterogeneity and polygenicity of all of these conditions and the difficulty of connecting multiple levels of molecular, cellular, and circuit functions to complex human behavior. Nevertheless, these advances place us on the threshold of a new frontier in the pathophysiological understanding, diagnosis, and treatment of psychiatric disease.

Although the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells show distinct layering. In the present study, we developed a high-content pipeline, the large-area spatial transcriptomic (LaST) map, which can quantify single-cell gene expression in situ. Screening 46 candidate genes for astrocyte diversity across the mouse cortex, we identified superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from those of neurons. Astrocyte layer features, established in the early postnatal cortex, mostly persisted in adult mouse and human cortex. Single-cell RNA sequencing and spatial reconstruction analysis further confirmed the presence of astrocyte layers in the adult cortex. Satb2 and Reeler mutations that shifted neuronal post-mitotic development were sufficient to alter glial layering, indicating an instructive role for neuronal cues. Finally, astrocyte layer patterns diverged between mouse cortical regions. These findings indicate that excitatory neurons and astrocytes are organized into distinct lineage-associated laminae.A new spatial transcriptomic approach reveals astrocyte heterogeneity across layers of the mammalian cerebral cortex. Astrocytes diversify into superficial-, mid- and deep-layer subtypes distinct from neuronal laminae, yet instructed by neuronal cues.

Key Points Over the past 5 years, researchers have identified many genetic factors that increase the risk of autism spectrum disorder (ASD), and that might shed light on more-homogeneous subgroups within the spectrum The most robustly identified genetic risks for ASD are rare mutations with large effect; studies have been underpowered to detect common genetic variation The role of rare genetic variants supports the relevance of studying monogenic disorders, such as tuberous sclerosis complex, for understanding ASD pathophysiology The most parsimonious explanation for the male predominance in ASD involves the presence of protective factors that reduce the risk of ASD in females Many genetic mutations associated with ASD also confer high risk of comorbidities including epilepsy, motor impairment and sleep disturbance Genetic testing including chromosomal microarray analysis is warranted and clinically indicated for all suspected cases of ASD Considerable phenotypic and genetic heterogeneity exists among the neurodevelopmental disorders described by the term autism spectrum disorder (ASD), which presents a challenge to treatment. Shafali and Geschwind outline the latest advances in genetic methods to identify and detect ASD-associated variants, and consider three themes—single-gene disorders, the gender bias in ASD, and neurological comorbidites—that could enable improved definition of ASD subgroups and understanding of disease aetiology. Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes—single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities—that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment.

Autism spectrum disorder, a common neurodevelopmental disorder with onset in infancy, is characterized by deficits in social functioning and by repetitive–restrictive behaviors, such as repeated body movements, circumscribed interests, or resistance to change in routines. Pharmacologic interventions are limited to the treatment of symptoms, which does not target social deficits. Although behavioral treatments have been effective in improving social and educational outcomes in some persons with autism spectrum disorder, there remains a need for the development of drugs that improve social functioning. The potential of the neuropeptide oxytocin as a “pro-social” hormone has gained attention for the treatment of autism . . .

Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.

Autism spectrum disorder (ASD) is more prevalent in males, and the mechanisms behind this sex-differential risk are not fully understood. Two competing, but not mutually exclusive, hypotheses are that ASD risk genes are sex-differentially regulated, or alternatively, that they interact with characteristic sexually dimorphic pathways. Here we characterized sexually dimorphic gene expression in multiple data sets from neurotypical adult and prenatal human neocortical tissue, and evaluated ASD risk genes for evidence of sex-biased expression. We find no evidence for systematic sex-differential expression of ASD risk genes. Instead, we observe that genes expressed at higher levels in males are significantly enriched for genes upregulated in post-mortem autistic brain, including astrocyte and microglia markers. This suggests that it is not sex-differential regulation of ASD risk genes, but rather naturally occurring sexually dimorphic processes, potentially including neuron–glial interactions, that modulate the impact of risk variants and contribute to the sex-skewed prevalence of ASD. Autism spectrum disorder is approximately 4.5 times more likely to occur in boys than girls. Here, Werling, Geschwind and Parikshak characterized sexually dimorphic gene expression in the non-diseased, post-mortem, adult and prenatal human brain, and show genes expressed at higher levels in males are significantly enriched for genes upregulated in autistic brain.

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.Schork et al. identify novel variants contributing to shared risk among psychiatric disorders and suggest that these variants act through the disruption of early neurodevelopment.

Key Points When applying high-throughput molecular methods to the study of neurodevelopmental disorders, major challenges include the spatial and temporal heterogeneity of the brain, a lack of appropriate tissue available for studies and poorly defined phenotypes. Transcriptomics assays are currently the most widely used functional genomic assays in neurobiology owing to their ability to efficiently capture tissue-specific spatial and temporal heterogeneity in a high-throughput manner. Principles from transcriptomic studies will aid in evaluating additional molecular and cellular levels of regulation. We review the principles of network analysis and describe how gene networks provide a framework to organize, integrate and analyse large-scale genomic data sets in neurobiology. We review representative differential expression and gene network studies in neurodevelopmental disorders and neurodegenerative diseases and identify some next steps in data generation and integration that are necessary for progress in the field. We provide guidelines for designing, analysing and evaluating high-throughput transcriptomic studies in the brain in order to improve study quality and reproducibility. The study of the genetic basis of neurodevelopmental disorders and neurodegenerative diseases has progressed through recent large-scale association studies as well as the application of a range of high-throughput molecular methods. In this Review, the authors examine systems biology approaches and demonstrate how gene networks provide an organizing framework to integrate the analysis of large-scale genetic and molecular profiling data sets to characterize the genetic basis of phenotypes that affect the central nervous system. Genetic and genomic approaches have implicated hundreds of genetic loci in neurodevelopmental disorders and neurodegeneration, but mechanistic understanding continues to lag behind the pace of gene discovery. Understanding the role of specific genetic variants in the brain involves dissecting a functional hierarchy that encompasses molecular pathways, diverse cell types, neural circuits and, ultimately, cognition and behaviour. With a focus on transcriptomics, this Review discusses how high-throughput molecular, integrative and network approaches inform disease biology by placing human genetics in a molecular systems and neurobiological context. We provide a framework for interpreting network biology studies and leveraging big genomics data sets in neurobiology.

Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons 1 – 4 . Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal—but not adult—microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system. In neonatal mice, scar-free healing after spinal cord injury is organized by microglia, and transplantation of neonatal microglia or peptidase-inhibitor-treated adult microglia into adult mice after injury improves healing and axon regrowth.