Search

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

A genome-wide-association meta-analysis of 18,381 austim spectrum disorder (ASD) cases and 27,969 controls identifies five risk loci. The authors find quantitative and qualitative polygenic heterogeneity across ASD subtypes.

A study leveraging transsynaptic tracing demonstrates rapid and extensive integration of human glioblastoma organoids into the mouse brain.

Here the authors identify TNIP1 as a risk factor for a fatal neurodegenerative disorder and discover specific genetic loci associated with the three main subtypes of this disorder. The findings highlight distinct disease mechanisms, emphasizing the roles of immunity and the notch signaling pathway.

Gordon et al. use genome-wide unbiased approaches to show that human cerebral cortical organoids, when cultured for many months, start to resemble stages of postnatal brain development, with a timeline that parallels in vivo development.

Saloner et al. used large-scale cerebrospinal fluid proteomics to uncover molecular signatures in frontotemporal dementia, revealing RNA splicing and synaptic protein candidate markers for genetic and sporadic disease progression.

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.

The authors present the largest genome-wide association study to date for a rare Parkinsonian disorder, progressive supranuclear palsy (PSP). They include follow-up investigations of the identified susceptibility loci, functional consequences, and cell-specific pathologies, providing insights into genetic and molecular mechanisms underlying PSP.

Zhang et al. performed a multi-regional multi-omics study, identifying brain-wide mitochondrial and synaptic defects in neurons and glial inflammation as key mechanisms underlying central nervous system impairment in COVID-19, potentially triggering neurodegeneration.

Cell-type-specific chromatin accessibility QTL during neurogenesis allow fine mapping of causal variants and more complete underlying of regulatory mechanisms underlying noncoding loci associated with gene expression and neuropsychiatric disorders.

The postgenomic era has seen important advances in the ability to perform large-scale analysis, using microarrays, of the genome at the level of gene sequence, gene copy number and messenger RNA transcript expression. In this review, Coppola and Geschwind discuss how microarray technology is being used to study of the genetics and pathogenesis of neurological disorders, and how it might be used in the future for patient diagnosis and classification into treatment groups.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

High-resolution three-dimensional maps of chromatin contacts in the developing human brain help to identify enhancer–promoter contacts, many of which are associated with human cognitive function and disease.

Here the authors couple an integrative genomic analysis with substantial in vitro and in vivo experimental validation, identifying REST as a novel suppressor of a pro-regenerative gene program and CNS axon regeneration in mice.

The gut-derived molecule 4-ethylphenol influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.

Studies of cell heterogeneity in white matter in primates have been limited to date. Here the authors describe a marmoset brain cell atlas that bridges rodent and human data, revealing strong gray-white matter glial segregation.

Although structural variation has been previously associated with autism spectrum disorders, this study reports a genome-wide significant association of common variants with susceptibility to this disorder group. The results implicate neuronal cell-adhesion molecules in the pathogenesis of this group of neurodevelopmental and neuropsychiatric disorders.

A genome-wide association study for attention deficit/hyperactivity disorder (ADHD) identifies 12 loci and implicates neurodevelopmental pathways and conserved regions of the genome as being involved in underlying ADHD biology.

Comprehensive factor analysis of core diagnostic features provides insights into the complex genetic architecture underlying phenotypic heterogeneity in autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with repetitive and restrictive behaviours. Here the authors integrate mRNA expression, miRNA expression, DNA methylation, and histone acetylation datasets from a collection of post mortem brain tissues and identify a convergent molecular subtype of ASD.

Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.

The authors analyzed the whole-exome sequences of over 16,000 individuals and found that very rare variants predicted to disrupt the SETD1A gene confer substantial risk for schizophrenia. Damaging variants in SETD1A were also associated with diverse, severe developmental disorders, providing an important genetic link between schizophrenia and other neurodevelopmental disorders.

Epigenomic profiling and massively parallel reporter assays identify 892 functional differentially-active single-nucleotide variants (daSNVs) linked to ten neuropsychiatric diseases. CRISPRi and gene editing approaches show magnesium transport dysfunction as a common genetic pathomechanism.

Empirically based models of disease progression in familial frontotemporal dementia reveal the relative ordering of clinical, neuroimaging, and fluid biomarker changes and facilitate novel clinical trial designs

Two new studies provide experimental evidence of how ancient genomic duplications of synaptic genes provided the substrate for diversification that ultimately expanded vertebrate cognitive complexity.

In this study, the authors develop a comprehensive taxonomy of brain-wide SPNs, identifying several novel subsets via their transcriptional signatures.

Mouse models show that myelin dysfunction and associated inflammation increase with age, which can promote amyloid-β deposition and therefore risk of developing Alzheimer’s disease.

Human MEF2C haploinsufficiency results in Autism Spectrum Disorder (ASD), but it is unclear if the same is true in mice. Here, the authors show that Mef2c ^+/− mice have behavioral defects and neuronal abnormalities similar to ASD, and symptoms can be ameliorated with the new drug, NitroSynapsin.

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.

The placenta has been proposed to be potentially relevant to schizophrenia risk. Here, the authors use the genetically predicted transcriptome to identify genes expressed in the placenta that could be involved in schizophrenia.

Therapeutic stress induces phenotypic plasticity in glioma stem cells although the mechanisms underlying this remain poorly understood. Here, the authors show that P300 mediates the radiation-induced vascular-like conversion of glioma stem cells to promote tumor recurrence.

The cellular heterogeneity in brain obscures the identification of robust cellular regulatory networks. Here the authors integrate genome-wide chromosome conformation data from sorted neurons and glia, with transcriptomic and enhancer profiles, to characterize cell-type-specific gene regulatory landscapes in the human brain, and provide insights into cell-type-specific gene regulatory networks in brain disorders.

A transcriptome-wide association study integrating genome-wide association data with expression data from brain, blood and adipose tissues identifies new candidate susceptibility genes for schizophrenia, providing a step toward understanding the underlying biology.

Genome-wide analyses yield insights into the polygenic effects contributing to clinical heterogeneity in attention deficit hyperactivity disorder, advancing understanding of its genetic etiology and serving as a model for future studies in other complex disorders.

Early cancer detection by cell-free DNA (cfDNA) is challenged by the low amount of tumour DNA in cfDNA, tumour heterogeneity and the small patient cohorts. Here, the authors develop a method, cfMethyl-Seq, for cost-effective methylome profiling of cfDNA and for detecting and locating cancer.

A new GWAS of schizophrenia (11,260 cases and 24,542 controls) and meta-analysis identifies 50 new associated loci and 145 loci in total. The common variant association signal is highly enriched in mutation-intolerant genes and in regions under strong background selection.

Genome-wide association analyses of magnetic resonance imaging data describe the genetic architecture of 13 cortical phenotypes at both global and regional levels, implicating neurodevelopmental and constrained genes.

Laser microdissection and microarrays are used to assess 900 precise subdivisions of the brains from three healthy men with 60,000 gene expression probes; the resulting atlas allows comparisons between humans and other animals, and will facilitate studies of human neurological and psychiatric diseases.

RNA sequencing reveals widespread transcriptomic changes across the cerebral cortex in autism spectrum disorder, including primary sensory regions, in addition to association regions, as well as an attenuation of regional identity.

Astrocytes are important players in brain development, homeostasis, and disease. Here, the authors compare the transcriptional profiles of human and mouse astrocytes. They report species-specific susceptibility to oxidative stress and response to hypoxic and inflammatory conditions.

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.