Biology subjects

Bray, N. J.

Publications and source records attributed to Bray, N. J..

8 recordsLinked to original sources

bioRxiv2026

drugMR: A multi-omics pipeline for genetically anchored drug-target discovery

Motivation: Genetically supported drug targets are an estimated 2.6 times more likely to succeed clinically, yet a disease association alone does not show which protein to target, in which direction, or what other effects may follow. This currently requires chaining separate tools. Results: drugMR is a Nextflow pipeline that, from GWAS and pQTL summary statistics, runs cis-Mendelian randomisation, colocalisation, SMR-HEIDI with bulk and/or single-cell QTLs, three-trait colocalisation and a phenome-wide screen for adverse effects and repurposing. Datasets are added through a manifest, every step runs in containers on a laptop, cluster or cloud, and results are explored in a dashboard. Applied to schizophrenia with brain pQTLs, drugMR tested 2,019 proteins in 4 h 19 min and prioritised 58 proteogenomic targets, 22 with multi-omic support; 4 had potential adverse effects. Availability and implementation: drugMR: https://github.com/guillermocomesanacimadevila/drugMR; documentation: https://guillermocomesanacimadevila.github.io/drugMR/. Demo data: https://doi.org/10.5281/zenodo.22917384.

bioinformatics↗

bioRxiv2025

Developmental, neuroanatomical and cellular expression of genes causing dystonia

ObjectiveDystonia is one of the most common forms of movement disorder with >50 genes identified as causative. However, an understanding of which developmental stages, brain regions and cell types are most relevant is crucial for developing relevant disease models and therapeutics. One approach is to examine the timing and anatomical expression of dystonia-causing genes, on the assumption that deleterious variants have a greater impact where higher levels of expression are observed. MethodsWe investigated the expression patterns of 44 dystonia-causing genes across two bulk- and two single-nuclei RNA-sequencing datasets, derived from prenatal and postnatal human brain tissue. ResultsDystonia genes were most strongly enriched in those with higher expression in the striatum, cerebral cortex, hippocampus, amygdala and substantia nigra, and for higher postnatal expression. Individual genes exhibiting differences in expression across adult brain regions include SQSTM1, SGCE, KMT2B, PRKRA, YY1, DNAJC12, KCNA1, CACNA1A (highest expression in cerebellum), ADCY5, GNAL, ANO3 (highest expression in striatum), RHOBTB2, FOXG1 (highest expression in cerebral cortex). Single-nuclei RNA-sequencing data analyses from human frontal cortex, striatum and cerebellum indicated that dystonia genes are predominantly expressed in neurons (both glutamatergic and GABAergic), rather than glia. Gene Ontology analysis showed prominent enrichment in biological processes such as dopamine biosynthetic and metabolic processes, and in the cellular components axons, presynapse and neuron projection. InterpretationThese analyses provide important insights into the anatomical, developmental and cellular expression patterns of dystonia-causing genes, potentially guiding the development of disease-relevant models and improving the timing and targeting of future therapeutic interventions.

neuroscience↗

bioRxiv2021

Sites of active gene regulation in the prenatal frontal cortex and their role in neuropsychiatric disorders

Common genetic variation appears to largely influence risk for neuropsychiatric disorders through effects on gene regulation. It is therefore possible to shed light on the biology of these conditions by testing for enrichment of associated genetic variation within regulatory genomic regions operating in specific tissues or cell types. Here, we have used ATAC-Seq to map open chromatin (an index of active regulatory genomic regions) in bulk tissue, NeuN+ and NeuN- nuclei from the prenatal human frontal cortex, and tested enrichment of SNP heritability for 5 neuropsychiatric disorders (autism spectrum disorder, ADHD, bipolar disorder, major depressive disorder and schizophrenia) within these regions. We observed significant enrichment of SNP heritability for ADHD, major depressive disorder and schizophrenia within open chromatin regions mapped in bulk fetal frontal cortex, and for all 5 tested neuropsychiatric conditions when we restricted these sites to those overlapping histone modifications indicative of enhancers (H3K4me1) or promoters (H3K4me3) in fetal brain. SNP heritability for neuropsychiatric disorders was significantly enriched in open chromatin regions identified in fetal frontal cortex NeuN- as well as NeuN+ nuclei overlapping fetal brain H3K4me1 or H3K4me3 sites. We additionally demonstrate the utility of our mapped open chromatin regions for prioritizing potentially functional SNPs at genome-wide significant risk loci for neuropsychiatric disorders. Our data provide evidence for an early neurodevelopmental component to a range of neuropsychiatric conditions and highlight an important role for regulatory genomic regions active within both NeuN+ and NeuN- cells of the prenatal brain.

genetics↗

bioRxiv2020

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

Alternative splicing is a post-transcriptional regulatory mechanism producing multiple distinct mRNA molecules from a single pre-mRNA. Alternative splicing has a prominent role in the central nervous system, impacting neurodevelopment and various neuronal functions as well as being increasingly implicated in brain disorders including autism, schizophrenia and Alzheimers disease. Standard short-read RNA-Seq approaches only sequence fragments of the mRNA molecule, making it difficult to accurately characterize the true nature of RNA isoform diversity. In this study, we used long-read isoform sequencing (Iso-Seq) to generate full-length cDNA sequences and map transcript diversity in the human and mouse cerebral cortex. We identify widespread RNA isoform diversity amongst expressed genes in the cortex, including many novel transcripts not present in existing genome annotations. Alternative splicing events were found to make a major contribution to RNA isoform diversity in the cortex, with intron retention being a relatively common event associated with nonsense-mediated decay and reduced transcript expression. Of note, we found evidence for transcription from novel (unannotated genes) and fusion events between neighbouring genes. Although global patterns of RNA isoform diversity were found to be generally similar between human and mouse cortex, we identified some notable exceptions. We also identified striking developmental changes in transcript diversity, with differential transcript usage between human adult and fetal cerebral cortex. Finally, we found evidence for extensive isoform diversity in genes associated with autism, schizophrenia and Alzheimers disease. Our data confirm the importance of alternative splicing in the cerebral cortex, dramatically increasing transcriptional diversity and representing an important mechanism underpinning gene regulation in the brain. We provide this transcript level data as a resource to the scientific community.

genomics↗

bioRxiv2020

Novel epigenetic clock for fetal brain development predicts fetal epigenetic age for iPSCs and iPSC-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. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and iPSC-derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.

neuroscience↗

bioRxiv2018

Sex differences in gene expression in the human fetal brain

Widespread structural, chemical and molecular differences have been reported between the male and female human brain. Although several neurodevelopmental disorders are more commonly diagnosed in males, little is known regarding sex differences in early human brain development. Here, we used RNA sequencing data from a large collection of human brain samples from the second trimester of gestation (N = 120) to assess sex biases in gene expression within the human fetal brain. In addition to 43 genes (102 Ensembl transcripts) transcribed from the Y-chromosome in males, we detected sex differences in the expression of 2558 autosomal genes (2723 Ensembl transcripts) and 155 genes on the X-chromosome (207 Ensembl transcripts) at a false discovery rate (FDR) < 0.1. Genes exhibiting sex-biased expression in human fetal brain are enriched for high-confidence risk genes for autism and other developmental disorders. Male-biased genes are enriched for expression in neural progenitor cells, whereas female-biased genes are enriched for expression in Cajal-Retzius cells and glia. All gene- and transcript-level data are provided as an online resource (available at http://fgen.psycm.cf.ac.uk/FBSeq1) through which researchers can search, download and visualize data pertaining to sex biases in gene expression during early human brain development.

genomics↗

bioRxiv2018

Novel Insight into the Aetiology of Autism Spectrum Disorder Gained by Integrating Expression Data with Genome-wide Association Statistics

BackgroundA recent genome-wide association study (GWAS) of autism spectrum disorders (ASD) (Ncases=18,381, Ncontrols=27,969) has provided novel opportunities for investigating the aetiology 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).\n\nMethodsUsing FUSION software, ASD GWAS summary statistics were integrated with predictors of gene expression from 16 human datasets, including adult and fetal brain. A novel adaptation of established statistical methods was then used to test for enrichment within candidate pathways, specific tissues, and at different stages of brain development. The proportion of ASD heritability explained by predicted expression of genes in the TWAS was estimated using stratified linkage disequilibrium-score regression.\n\nResultsThis study identified 14 genes as significantly differentially expressed in ASD, 13 of which were outside of known genome-wide significant loci ({+/-}500kb). XRN2, a gene proximal to an ASD GWAS locus, was inferred to be significantly upregulated in ASD, providing insight into functional consequence of this associated locus. One novel transcriptome-wide significant association from this study is the downregulation of PDIA6, which showed minimal evidence of association in the GWAS, and in gene-based analysis using MAGMA. Predicted gene expression in this study accounted for 13.0% of the total ASD SNP-heritability.\n\nConclusionThis study has implicated several genes as significantly up-/down-regulated in ASD providing novel and useful information for subsequent functional studies. This study also explores the utility of TWAS-based enrichment analysis and compares TWAS results with a functionally agnostic approach.

genomics↗

bioRxiv2018

Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

Genome-wide significant variants associated with combined risk for major psychiatric disorders on chromosome 10q24 affect the expression of the cytosolic 5-nucleotidase II (NT5C2, cN-II) in population controls, implicating it as a psychiatric susceptibility gene. Risk alleles are associated with reduced expression of this gene in the developing and adult brain, but the resulting neurobiological risk mechanisms remain elusive. In this study, we provide further evidence for the association of NT5C2 with psychiatric disorders, and use a functional genetics approach to gain a deeper understanding of the function of this risk gene in the nervous system. NT5C2 expression was significantly reduced in the post-mortem brain of schizophrenia and bipolar disorder patients, and its protein predominately expressed in neurons within the adult brain. Using human neural progenitor cells (hNPCs), we found that NT5C2 expression peaked at the neural progenitor state, where the encoded protein was ubiquitously distributed through the cell. NT5C2 knockdown in hNPCs elicited transcriptomic changes associated with protein translation, that were accompanied by regulation of adenosine monophosphate-activated protein kinase (AMPK) signalling and ribosomal protein S6 (rpS6) activity. To identify the effect of reduced neuronal NT5C2 expression at a systems level, we knockdown its homologue, CG32549, in Drosophila melanogaster CNS. This elicited impaired climbing behaviour in the model organism. Collectively, our data implicate NT5C2 expression in risk for psychiatric disorders and in Drosophila melanogaster motility, and further suggest that risk is mediated via regulation of AMPK signalling and protein translation during early neurodevelopment.

neuroscience↗