Genetic Implication of Specific Glutamatergic Neurons of the Prefrontal Cortex in the Pathophysiology of Schizophrenia.

Background: The prefrontal cortex (PFC) has been strongly implicated in the pathophysiology of schizophrenia. Here, we combined high-resolution single-nuclei RNA sequencing data from the human PFC with large-scale genomic data for schizophrenia to identify constituent cell populations likely to mediate genetic liability to the disorder.

Methods: Gene expression specificity values were calculated from a single-nuclei RNA sequencing dataset comprising 84 cell populations from the human PFC, spanning gestation to adulthood.

Genetic Implication of Prenatal GABAergic and Cholinergic Neuron Development in Susceptibility to Schizophrenia.

Background: The ganglionic eminences (GE) are fetal-specific structures that give rise to gamma-aminobutyric acid (GABA)- and acetylcholine-releasing neurons of the forebrain. Given the evidence for GABAergic, cholinergic, and neurodevelopmental disturbances in schizophrenia, we tested the potential involvement of GE neuron development in mediating genetic risk for the condition.

Study Design: We combined data from a recent large-scale genome-wide association study of schizophrenia with single-cell RNA sequencing data from the human GE to test the enrichment of schizophrenia risk variation in genes with high expression specificity for developing GE cell populations.

Her2 amplification, Rel-A, and Bach1 can influence APOBEC3A expression in breast cancer cells.

APOBEC-induced mutations occur in 50% of sequenced human tumors, with APOBEC3A (A3A) being a major contributor to mutagenesis in breast cancer cells. The mechanisms that cause A3A activation and mutagenesis in breast cancers are still unknown. Here, we describe factors that influence basal A3A mRNA transcript levels in breast cancer cells.

Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain.

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts.

Genetic implication of prenatal GABAergic and cholinergic neuron development in susceptibility to schizophrenia.

Background: The ganglionic eminences are fetal-specific structures that give rise to gamma-aminobutyric acid (GABA)- and acetylcholine- releasing neurons of the forebrain. Given evidence for GABAergic and cholinergic disturbances in schizophrenia, as well as an early neurodevelopmental component to the disorder, we tested the potential involvement of developing cells of the ganglionic eminences in mediating genetic risk for the condition.

Study Design: We combined data from a recent large-scale genome-wide association study of schizophrenia with single cell RNA sequencing data from the human ganglionic eminences to test enrichment of schizophrenia risk variation in genes with high expression specificity for particular developing cell populations within these structures.

Genetic inhibitors of APOBEC3B-induced mutagenesis.

The cytidine deaminases APOBEC3A (A3A) and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we used a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast.

Mapping microRNA expression quantitative trait loci in the prenatal human brain implicates miR-1908-5p expression in bipolar disorder and other brain-related traits.

MicroRNA (miRNA) are small non-coding RNA involved in post-transcriptional gene regulation. Given their known involvement in early neurodevelopment processes, we here sought to identify common genetic variants associated with altered miRNA expression in the prenatal human brain. We performed small RNA sequencing on brain tissue from 112 genome-wide genotyped fetuses from the second trimester of gestation, identifying high-confidence (false discovery rate < 0.

Genetic modifiers of APOBEC-induced mutagenesis.

The cytidine deaminases APOBEC3A and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we utilized a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast.

Cross-ancestry, cell-type-informed atlas of gene, isoform, and splicing regulation in the developing human brain.

Genomic regulatory elements active in the developing human brain are notably enriched in genetic risk for neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and bipolar disorder. However, prioritizing the specific risk genes and candidate molecular mechanisms underlying these genetic enrichments has been hindered by the lack of a single unified large-scale gene regulatory atlas of human brain development. Here, we uniformly process and systematically characterize gene, isoform, and splicing quantitative trait loci (xQTLs) in 672 fetal brain samples from unique subjects across multiple ancestral populations.

Single-Nuclei RNA Sequencing of 5 Regions of the Human Prenatal Brain Implicates Developing Neuron Populations in Genetic Risk for Schizophrenia.

Background: While a variety of evidence supports a prenatal component in schizophrenia, there are few data regarding the cell populations involved. We sought to identify cells of the human prenatal brain mediating genetic risk for schizophrenia by integrating cell-specific gene expression measures generated through single-nuclei RNA sequencing with recent large-scale genome-wide association study (GWAS) and exome sequencing data for the condition.

Methods: Single-nuclei RNA sequencing was performed on 5 brain regions (frontal cortex, ganglionic eminence, hippocampus, thalamus, and cerebellum) from 3 fetuses from the second trimester of gestation.

Schizophrenia Genomics: Convergence on Synaptic Development, Adult Synaptic Plasticity, or Both?

Large-scale genomic studies of schizophrenia have identified hundreds of genetic loci conferring risk to the disorder. This progress offers an important route toward defining the biological basis of the condition and potentially developing new treatments. In this review, we discuss insights from recent genome-wide association study, copy number variant, and exome sequencing analyses of schizophrenia, together with functional genomics data from the pre- and postnatal brain, in relation to synaptic development and function.

Full-length transcript sequencing of human and mouse cerebral cortex identifies widespread isoform diversity and alternative splicing.

Alternative splicing is a post-transcriptional regulatory mechanism producing distinct mRNA molecules from a single pre-mRNA with a prominent role in the development and function of the central nervous system. We used long-read isoform sequencing to generate full-length transcript sequences in the human and mouse cortex. We identify novel transcripts not present in existing genome annotations, including transcripts mapping to putative novel (unannotated) genes and fusion transcripts incorporating exons from multiple genes.

Exercise behaviors and resource use among graduate students at a Canadian university: A cross-sectional study.

Objective: Participation in regular exercise among post-secondary students is often low. Our cross-sectional study aimed to assess exercise levels, perceived barriers/motivators to exercise, and knowledge and use of exercise resources in graduate students.

Participants: We recruited graduate students across various disciplines at a large Canadian university.

CSF-resident CD4 T-cells display a distinct gene expression profile with relevance to immune surveillance and multiple sclerosis.

The CNS has traditionally been considered an immune privileged site, but is now understood to have a system of immune surveillance, predominantly involving CD4 T-cells. Identifying functional differences between CNS and blood CD4 T-cells, therefore, have relevance to CNS immune surveillance as well as to neurological conditions, such as multiple sclerosis, in which CD4 T-cells play a central role. Here, CD4 T-cells were purified from CSF and blood from 21 patients with newly diagnosed treatment-naïve multiple sclerosis and 20 individuals with non-inflammatory disorders using fluorescence-activated cell sorting, and their transcriptomes were profiled by RNA sequencing.

Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons.

Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age.

Polygenic risk for schizophrenia and subcortical brain anatomy in the UK Biobank cohort.

Research has shown differences in subcortical brain volumes between participants with schizophrenia and healthy controls. However, none of these differences have been found to associate with schizophrenia polygenic risk. Here, in a large sample (n = 14,701) of unaffected participants from the UK Biobank, we test whether schizophrenia polygenic risk scores (PRS) limited to specific gene-sets predict subcortical brain volumes.

Cis-effects on gene expression in the human prenatal brain associated with genetic risk for neuropsychiatric disorders.

The majority of common risk alleles identified for neuropsychiatric disorders reside in noncoding regions of the genome and are therefore likely to impact gene regulation. However, the genes that are primarily affected and the nature and developmental timing of these effects remain unclear. Given the hypothesized role for early neurodevelopmental processes in these conditions, we here define genetic predictors of gene expression in the human fetal brain with which we perform transcriptome-wide association studies (TWASs) of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, bipolar disorder, major depressive disorder, and schizophrenia.

No Effect of Genome-Wide Significant Schizophrenia Risk Variation at the Locus on the Allelic Expression of in Postmortem Striatum.

A genome-wide significant association has been reported between non-coding variants at the dopamine D2 receptor () gene locus and schizophrenia. However, effects of identified schizophrenia risk alleles on function are yet to be demonstrated. Using highly sensitive measures of allele-specific expression, we have assessed -regulatory effects associated with genotype at lead SNP rs2514218 on expression in the adult human striatum.

A transcriptome-wide association study implicates specific pre- and post-synaptic abnormalities in schizophrenia.

Schizophrenia is a complex highly heritable disorder. Genome-wide association studies (GWAS) have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. We identify a significant correlation between schizophrenia risk and expression at 89 genes in the dorsolateral prefrontal cortex (P ≤ 9.

Novel Insight Into the Etiology of Autism Spectrum Disorder Gained by Integrating Expression Data With Genome-wide Association Statistics.

Background: A recent genome-wide association study (GWAS) of autism spectrum disorder (ASD) (n = 18,381, n = 27,969) has provided novel opportunities for investigating the etiology of ASD. Here, we integrate the ASD GWAS summary statistics with summary-level gene expression data to infer differential gene expression in ASD, an approach called transcriptome-wide association study (TWAS).

Methods: Using FUSION software, ASD GWAS summary statistics were integrated with predictors of gene expression from 16 human datasets, including adult and fetal brains.

Transcriptional Changes following Cellular Knockdown of the Schizophrenia Risk Gene Are Enriched for Common Variant Association with the Disorder.

Loss of function mutations in are the first experiment-wide significant findings to emerge from exome sequencing studies of schizophrenia. Although is known to encode a histone methyltransferase, the consequences of reduced S activity on gene expression in neural cells have, to date, been unknown. To explore transcriptional changes through which genetic perturbation of could confer risk for schizophrenia, we have performed genome-wide gene expression profiling of a commonly used human neuroblastoma cell line in which expression has been experimentally reduced using RNA interference (RNAi).

The genetics of neuropsychiatric disorders.

Neuropsychiatric disorders are complex conditions with poorly defined neurobiological bases. In recent years, there have been significant advances in our understanding of the genetic architecture of these conditions and the genetic loci involved. This review article describes historical attempts to identify susceptibility genes for neuropsychiatric disorders, recent progress through genome-wide association studies, copy number variation analyses and exome sequencing, and how these insights can inform the neuroscientific investigation of these conditions.