Biology subjects

Reay, W. R.

Publications and source records attributed to Reay, W. R..

5 recordsLinked to original sources

bioRxiv2026

Towards standards for analysing structural variants from short-read whole genome sequencing data

No widely accepted standard exists for analysing structural variants from short-read whole genome sequencing (WGS) data. We use comprehensive SV truth sets (HG002 T2T-Q100, Platinum Pedigree) and long-read sequencing databases (1KGP-ONT, CoLoRS) to benchmark SV breakpoints and sizes at base pair resolution. Using 30X Illumina WGS data, only five of sixteen individual tools tested reliably output deletions, insertions and duplications that perfectly match the truth sets. Ensemble pipelines (e.g. GATK-SV, MOPline, Parliament2), frequently used in population-scale datasets, reduced perfect matching accuracy by up to 98% compared to their highest-performing constituent tools. This inaccuracy propagates into a short-read database (gnomAD-SV) constructed from an ensemble pipeline (GATK-SV) and likely affects other databases (TOPMed, All of Us, Biobank Japan). As a proof-of-concept, we demonstrate an intra-sample merging strategy that generates the highest F1-scores for deletions and insertions on the HG002 sample, recovering more perfect matches than total matches from the best performing ensemble pipeline tested. Common HG002 truth SVs (allele frequency > 1%) showed extremely high concordance for exact matches between our ensemble callset and two orthogonal long-read sequencing databases (CoLoRS, ONT-1KGP). This study provides a vital step towards robust standards for SV analysis, guiding short-read WGS ensemble pipeline development and improving cross-study comparisons.

genomics↗

bioRxiv2021

MicroRNA binding site variation is enriched inpsychiatric disorders

Psychiatric disorders and other complex traits have a polygenic architecture, often associated with dozens or even hundreds of independent genomic loci. As each of these have a relatively small influence on the trait, the dissection of their biological components is a non-trivial task. For psychiatric disorders in particular, the majority of associated loci lie within non-coding regions of the genome, suggesting that most of the genetic risk for disease originates from the disruption of regulatory sequences. While previously exploration of the heritability of these sequences has focused on variants that modify DNA elements, those that alter cis-acting RNA sequences, such as miRNA binding sites, are also likely to have a significant impact in these disorders. MiRNA have already been shown to be dysregulated in these disorders through both genetic and environmental influence, so it is reasonable to suspect their target genes may also be affected by common variation. In this study, we investigated the distribution of miRNA binding site variants (MBSVs) predicted to alter miRNA binding affinity in psychiatric disorders and observed significant enrichment in schizophrenia, depression, bipolar disorder, and anorexia nervosa. We also observed significant enrichment of MBSVs in genes targeted by several miRNA families, including miR-335-5p, miR-21-5p/590-5p, miR-361-5p, and miR-557 in both schizophrenia and depression, and nominally significant enrichment of MBSV for miR-323b-3p in schizophrenia. We also identified a significant association between MBSVs in gene sets involved in regulation of the synapse and synaptic depression in schizophrenia. While these observations support the role of miRNA in the pathophysiology of psychiatric disorders, we also observed significant association of MBSVs in other complex traits suggesting that MBSVs are an important class of regulatory variants that have functional implications for many disorders.

genetics↗

bioRxiv2020

Investigating the effect of glycaemic traits on the risk of psychiatric illness using Mendelian randomisation

Data from observational studies have suggested an involvement of abnormal glycaemic regulation in the pathophysiology of psychiatric illness. This may be an attractive target for clinical intervention as glycaemia can be modulated by both lifestyle factors and pharmacological agents. However, observational studies are inherently confounded, and therefore causal relationships cannot be reliably established. We employed genetic variants rigorously associated with three glycaemic traits (fasting glucose, fasting insulin, and glycated haemoglobin) as instrumental variables in a two-sample Mendelian randomisation analysis to investigate the causal effect of these measures on the risk for eight psychiatric disorders. A significant protective effect of a unit increase in fasting insulin levels was observed for anorexia nervosa after the application of multiple testing correction (OR = 0.48 [95% CI: 0.33-0.71] - inverse-variance weighted estimate. The relationship between fasting insulin and anorexia nervosa was supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between insulin levels and anorexia.

genetics↗

bioRxiv2019

Pairwise common variant meta-analyses of schizophrenia with other psychiatric disorders reveals shared and distinct gene and gene-set associations

The complex aetiology of schizophrenia is postulated to share factors with other psychiatric disorders. Recently, this has been supported by genome-wide association studies, with several psychiatric phenotypes displaying high genomic correlation with schizophrenia. We sought to investigate pleiotropy amongst the common variant genomics of schizophrenia and seven other psychiatric disorders using a multimarker test of association. Gene-based analysis of common variation revealed over 50 schizophrenia-associated genes shared with other psychiatric phenotypes; including bipolar disorder, major depressive disorder, ADHD, and autism spectrum disorder. In addition, we uncovered 78 genes significantly enriched with common variant associations for schizophrenia that were not linked to any of these seven disorders (P > 0.05). Transcriptomic imputation was then leveraged to investigate the functional significance of variation mapped to these genes, prioritising several interesting functional candidates. Pairwise meta-analysis of schizophrenia and each psychiatric phenotype further revealed 330 significantly associated genes (PMeta < 2.7 x 10-6) that were only nominally associated with each disorder individually (P < 0.05). Multivariable gene-set association suggested that common variation enrichment within biologically constrained genes observed for schizophrenia also occurs across several psychiatric phenotypes. These analyses consolidate the overlap between the genomic architecture of schizophrenia and other psychiatric disorders and uncovered several pleiotropic genes which warrant further investigation.\n\nAUTHOR SUMMARYSchizophrenia and other psychiatric disorders have many similarities, and this includes features of their overall genetic risk. Here, we investigate genes which may play a role in schizophrenia as well one or more of seven other psychiatric phenotypes and demonstrate that a number of them are pleiotropic and influence at least one other disorder. We also identify genes amongst the psychiatric disorders studied here which only show association with schizophrenia. Furthermore, we find a number of genes which were only significant when combining genetic association data from schizophrenia and one of the other seven disorders, suggesting there are shared genetic influences that are revealed through the power of joint analysis. This study identifies interesting novel shared (pleiotropic) genes in psychiatry which warrant future study.

genetics↗

bioRxiv2019

Pharmacological enrichment of polygenic risk for precision medicine in complex disorders

Individuals with complex disorders typically have a heritable burden of common variation that can be expressed as a polygenic risk score (PRS). While PRS has some predictive utility, it lacks the molecular specificity to be directly informative for clinical interventions. We therefore sought to develop a framework to quantify an individuals common variant enrichment in clinically actionable systems responsive to existing drugs. This was achieved with a metric designated the pharmagenic enrichment score (PES), which we demonstrate for individual SNP profiles in a cohort of cases with schizophrenia. A large proportion of these had elevated PES in one or more of eight clinically actionable gene-sets enriched with schizophrenia associated common variation. Notable candidates targeting these pathways included vitamins, insulin modulating agents, and protein kinase inhibitors with putative neuroprotective properties. Interestingly, elevated PES was also observed in individuals with otherwise low common variant burden. The biological saliency of PES profiles were observed directly through their impact on gene expression in a subset of the cohort with matched transcriptomic data, supporting our assertion that this framework can integrate an individuals common variant risk to inform personalised interventions, including drug repositioning, for complex disorders such as schizophrenia.

genetics↗