Biology subjects

Harwood, J. C.

Publications and source records attributed to Harwood, J. C..

4 recordsLinked to original sources

bioRxiv2020

Developmental profile of psychiatric risk associated with voltage-gated cation channel activity

BackgroundRecent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant. MethodsWe aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used post-mortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple pre- and post-natal timepoints and summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder and major depressive disorder. We prioritised gene sets for overall enrichment of association with each disorder, and then tested the relationship between the association of each of their constituent genes with their relative expression at each developmental stage. ResultsWe observed relationships between the expression of genes involved in voltage-gated cation channel activity during Early Midfetal, Adolescence and Early Adulthood timepoints and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during Early Midfetal development and higher expression during Adolescence and Early Adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, whilst for bipolar disorder the relationship was distributed between calcium and potassium channel activity genes. ConclusionsOur results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk to psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.

neuroscience↗

bioRxiv2020

Monocyte-specific changes in gene expression implicate LACTB2 and PLIN2 in Alzheimer's disease.

More than 50 genetic loci have been identified as being associated with Alzheimers disease (AD) from genome-wide association studies (GWAS) and many of these are involved in immune pathways and lipid metabolism. Therefore, we performed a transcriptome-wide association study (TWAS) of immune-relevant cells, to study the mis-regulation of genes implicated in AD. We used expression and genetic data from naive and induced CD14+ monocytes and two GWAS of AD to study genetically controlled gene expression in monocytes at different stages of differentiation and compared the results with those from TWAS of brain and blood. We identified nine genes with statistically independent TWAS signals, seven are known AD risk genes from GWAS: BIN1, PTK2B, SPI1, MS4A4A, MS4A6E, APOE and PVR and two, LACTB2 and PLIN2/ADRP, are novel candidate genes for AD. Three genes, SPI1, PLIN2 and LACTB2, are TWAS significant specifically in monocytes. LACTB2 is a mitochondrial endoribonuclease and PLIN2/ADRP associates with intracellular neutral lipid storage droplets (LSDs) which have been shown to play a role in the regulation of the immune response. Notably, LACTB2 and PLIN2 were not detected from GWAS alone.

neuroscience↗

bioRxiv2020

Genetic association of FMRP targets with psychiatric disorders

AO_SCPLOWBSTRACTC_SCPLOWGenes encoding the mRNA targets of Fragile X mental retardation protein (FMRP) are enriched for genetic association with psychiatric disorders. However, many FMRP targets possess functions that are themselves genetically associated with psychiatric disorders, including synaptic transmission and plasticity, making it unclear whether the genetic risk is truly related to binding by FMRP or is alternatively mediated by the sampling of genes better characterised by another trait or functional annotation. Using published common variant, rare coding variant and copy number variant data, we examined the relationship between FMRP binding and genetic association with schizophrenia, major depressive disorder and bipolar disorder. We then explored the partitioning of genetic association between overrepresented functional categories. High-confidence targets of FMRP were enriched for common schizophrenia risk alleles, as well as rare loss-of-function and de novo nonsynonymous variants in cases. Similarly, through common variation, FMRP targets were associated with major depressive disorder, and we present novel evidence of association with bipolar disorder. These relationships could not be explained by membership of other functional annotations known to be associated with psychiatric disorders, including those related to synaptic structure and function. This study reinforces the evidence that targeting by FMRP captures a subpopulation of genes enriched for genetic association with a range of psychiatric disorders, across traditional diagnostic boundaries.

neuroscience↗

bioRxiv2018

Nucleosome dynamics of human iPSC during the early stages of neurodevelopment

Regulation of nucleosome positioning is important for neurodevelopment, and mutation of genes mediating chromatin remodelling are strongly associated with human neurodevelopmental disorders. Unicellular organisms possess arrays of highly positioned nucleosomes within their chromatin, occupying up to 80% of their genomes. These span gene-coding and regulatory regions, and can be associated with local changes of gene transcription. In the much larger genome of human cells, the roles of nucleosome positioning are less clear, and this raises questions of how nucleosome dynamics interfaces with human neurodevelopment.\n\nWe have generated genome-wide nucleosome maps from an undifferentiated human induced pluripotent stem cell (hiPSC) line and after its differentiation to the neuronal progenitor cell (NPC) stage. We found that approximately 3% of nucleosomes are highly positioned in NPC. In contrast, there are 8-fold less positioned nucleosomes in pluripotent cells, with the majority arising de novo or relocating during cell differentiation. Positioned nucleosomes do not directly correlate with active chromatin or gene transcription, such as marking Transcriptional Start Sites (TSS). Unexpectedly, we find a small population of nucleosomes that remain positioned after differentiation, occupying similar positions in pluripotent and NPC cells. They flank the binding sites of the key gene regulators NRSF/REST and CTCF, but remain in place whether or not their regulatory complexes are present. Together, these results present an alternative view in human cells, where positioned nucleosomes are sparse and dynamic, but act to alter gene expression at a distance via structural conformation at sites of chromatin regulation, not local changes in gene organisation.

genomics↗