Our multidisciplinary team works across a variety of research projects that are reflected through our list of publications (displayed by publication date):
A molecular map of the living human brain from quantitative MRI
Melissa Grant-Peters, George E C Thomas, Daan van Kruining, Louise A Huuki-Myers, Ruth Zhang, Jonathan W Brenton, Hemanth Nelvagal, Angelika Zarkali, James R Evans, Christina E Toomey, Aine Fairbrother-Browne, Ivelina Dobreva, Kelsey D Montgomery, Joanne Lachica, Naomi Hannaway, Nicholas Wood, Sonia Gandhi, Martina F Callaghan, Frances Platt, Zane Jaunmuktane, Karin Shmueli, Leonardo Collado-Torres, Kristen R Maynard, Rimona S Weil, Mina Ryten
We introduce a non-invasive imaging framework that integrates ultra-high-resolution 7T quantitative MRI (qMRI) with spatially-resolved transcriptomics (SRT) to infer cell-type and pathway-specific molecular features within the cortical grey matter. This proof-of-concept establishes the integration of qMRI and SRT as a scalable, non-invasive platform for molecular profiling in neurodegeneration, with significant potential for precision therapeutic monitoring, drug development and clinical trials.
bioRxiv 2025.09.24.678316;
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TDP-43 loss of function drives aberrant splicing in Parkinson's disease
Jonathan W. Brenton, Jordan Follett, Raja Nirujogi, Christina E. Toomey, Patricia Lopez-Garcia, James R. Evans, Yeon J. Lee, Khaja Mohieddin Syed, Guillermo Rocamora Perez, Áine Fairbrother-Browne, Karishma D'Sa, Melissa Grant-Peters, Joanne Lachica, Amy R. Hicks, Aaron Z. Wagen, Benjamin O'Callaghan, Hannah Macpherson, Kylie-ann Montgomery, Oriol Busquets, Regina H. Reynolds, Sonia Garcia Ruiz, Tianyu Cao, Zhongbo Chen, Hélène Plun-Favreau, Philip C. Wong, Matthew Farrer, Tammaryn Lashley, Frank Soldner, Dirk Hockemeyer, Dario Alessi, Nicholas W. Wood, John Hardy, Donald C. Rio, Zane Jaunmuktane, Emil K. Gustavsson, Sonia Gandhi, Mina Ryten
TDP-43 is a RNA-binding protein encoded by TARDBP that plays a critical role in RNA processing. Loss of TDP-43 function and its cytoplasmic aggregation are hallmarks of TDP-43 proteinopathies including ALS and FTLD, but also occur in a proportion of Parkinson's disease (PD) cases. Here we investigate the impact of TDP-43 loss of function on splicing in the context of PD, identifying aberrant splicing events that are enriched for PD-associated genes and highlight potential therapeutic targets.
bioRxiv 2025.09.04.673943;
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Molecular and cellular signatures differentiate Parkinson's disease from Parkinson's disease with dementia
Aine Fairbrother-Browne, Melissa Grant-Peters, Jonathan W. Brenton, Hemanth Nelvagal, Regina Reynolds, Yau Mun Lim, Emil K Gustavsson, Hannah Macpherson, Kylie Montgomery, James R. Evans, Amy R Hicks, Nancy Chiraki, Toby Curless, Raquel Real, Theodoros Xenakis, Henry Houlden, Huw R Morris, Sonia Gandhi, Nicholas W. Wood, John Hardy, Zane Jaunmuktane, Mina Ryten
Parkinson's disease (PD) and Parkinson's disease with dementia (PDD) are closely related but clinically distinct conditions. Here we use transcriptomic profiling to identify molecular and cellular signatures that differentiate PD from PDD, providing insights into the biological processes that underlie the transition from PD to PDD and highlighting potential targets for therapeutic intervention.
bioRxiv 2025.03.04.641379;
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Astrocytic RNA editing regulates the host immune response to alpha-synuclein
Karishma D'Sa, Minee L Choi, Aaron Z Wagen, Núria Setó-Salvia, Olga Kopach, James R Evans, Margarida Rodrigues, Patricia Lopez-Garcia, Joanne Lachica, Benjamin E Clarke, Jaijeet Singh, Ali Ghareeb, James Bayne, Melissa Grant-Peters, Sonia Garcia-Ruiz, Zhongbo Chen, Samuel Rodriques, Dilan Athauda, Emil K Gustavsson, Sarah A Gagliano Taliun, Christina Toomey, Regina H Reynolds, George Young, Stephanie Strohbuecker, Thomas Warner, Dmitri A Rusakov, Rickie Patani, Clare Bryant, David A Klenerman, Sonia Gandhi, Mina Ryten
RNA editing is a posttranscriptional mechanism that targets changes in RNA transcripts to modulate innate immune responses. We report the role of astrocyte-specific, ADAR1-mediated RNA editing in neuroinflammation in Parkinson's disease (PD). We generated human induced pluripotent stem cell-derived astrocytes, neurons and cocultures and exposed them to small soluble alpha-synuclein aggregates. Oligomeric alpha-synuclein triggered an inflammatory glial state associated with Toll-like receptor activation, viral responses, and cytokine secretion. This reactive state resulted in loss of neurosupportive functions and the induction of neuronal toxicity. Notably, interferon response pathways were activated leading to up-regulation and isoform switching of the RNA deaminase enzyme, ADAR1. ADAR1 mediates A-to-I RNA editing, and increases in RNA editing were observed in inflammatory pathways in cells, as well as in postmortem human PD brain. Aberrant, or dysregulated, ADAR1 responses and RNA editing may lead to sustained inflammatory reactive states in astrocytes triggered by alpha-synuclein aggregation, and this may drive the neuroinflammatory cascade in Parkinson's.
Science Advances; 11 Apr 2025; Vol 11, Issue 15
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PSQAN: a pipeline to prioritize novel and biologically relevant transcripts from long-read RNA sequencing
Siddharth Sethi, Emil K Gustavsson, Harpreet Saini, Mina Ryten
Long-read RNA sequencing has the potential to accurately quantify transcriptomes and reveal the isoform diversity of disease-causing genes. However, despite the recent advances in analysis tools for transcript discovery, long-read RNA sequencing data is still challenging to analyse, due to the detection of hundreds or even thousands of novel transcripts per gene. Here, we introduce PSQAN, a workflow to help researchers prioritize high-confidence and potentially biologically relevant transcripts associated with candidate genes and make transcript characterization results more interpretable.
Bioinformatics Advances; 20 Nov 2025; Vol 5, Issue 1
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Splicing accuracy varies across human introns, tissues, age and disease
S García-Ruiz, D Zhang, E K Gustavsson, G Rocamora-Perez, M Grant-Peters, A Fairbrother-Browne, R H Reynolds, J W Brenton, A L Gil-Martínez, Z Chen, D C Rio, J A Botia, S Guelfi, L Collado-Torres, M Ryten
Alternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigate splicing accuracy using RNA-sequencing data from >14k control samples and 40 human body sites, focusing on split reads partially mapping to known transcripts in annotation. We show that splicing inaccuracies occur at different rates across introns and tissues and are affected by the abundance of core components of the spliceosome assembly and its regulators. We find that age is positively correlated with a global decline in splicing fidelity, mostly affecting genes implicated in neurodegenerative diseases.
Nature Communications; 27 Jan 2025; Vol 16, Issue 1, Article 1068
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Network nature of ligand-receptor interactions underlies disease comorbidity in the brain
Melissa Grant-Peters, Aine Fairbrother-Browne, Amy Hicks, Boyi Guo, Regina H. Reynolds, Louise Huuki-Myers, Nick Eagles, Jonathan Brenton, Sonia Garcia-Ruiz, Nicholas Wood, Sonia Gandhi, Kristen Maynard, Leonardo Collado-Torres, Mina Ryten
Neurodegenerative disorders have overlapping symptoms and have high comorbidity rates, but this is not reflected in overlaps of risk genes. We have investigated whether ligand-receptor interactions (LRIs) are a mechanism by which distinct genes associated with disease risk can impact overlapping outcomes. We found that LRIs are likely disrupted in neurological disease and that the ligand-receptor networks associated with neurological diseases have substantial overlaps. Specifically, 96.8% of LRIs associated with disease risk are interconnected in a single LR network. These ligands and receptors are enriched for roles in inflammatory pathways and highlight the role of glia in cross-disease risk. Disruption to this LR network due to disease-associated processes (e.g. differential transcript use, protein misfolding) is likely to contribute to disease progression and risk of comorbidity. Our findings have implications for drug development, as they highlight the potential benefits and risks of pursuing cross-disease drug targets.
bioRxiv 2024.06.15.599140;
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The diversity of SNCA transcripts in neurons, and its impact on antisense oligonucleotide therapeutics
James R. Evans, Emil K. Gustavsson, Ivan Doykov, David Murphy, Gurvir S. Virdi, Joanne Lachica, Alexander Röntgen, Mhd Hussein Murtada, Chun Wei Pang, Hannah Macpherson, Anna I. Wernick, Christina E. Toomey, Dilan Athauda, Minee L. Choi, John Hardy, Nicholas W. Wood, Michele Vendruscolo, Kevin Mills, Wendy Heywood, Mina Ryten, Sonia Gandhi
The role of the SNCA gene locus in driving Parkinson's disease (PD) through rare and common genetic variation is well-recognized, but the transcriptional diversity of SNCA in vulnerable cell types remains unclear. We performed SNCA long-read RNA sequencing in human dopaminergic neurons and show that annotated SNCA transcripts account for only 5% of expression. Rather, the majority of expression (75%) at the SNCA locus originates from transcripts with alternative 5' and 3' untranslated regions. Importantly, 10% originates from transcripts encoding open reading frames not previously annotated, which are translated and detectable in human postmortem brain. Defining the 3' untranslated regions enabled the rational design of antisense oligonucleotides targeting the majority of SNCA transcripts, leading to the effective reversal of PD pathology, including protein aggregation, mitochondrial dysfunction, and toxicity. Resolving the complexity of the SNCA transcriptional landscape impacts RNA therapies and highlights differences in protein isoforms and their contribution to disease.
bioRxiv 2024.05.30.596437;
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Ancestry-specific gene expression in peripheral monocytes mediates risk of neurodegenerative disease
Aaron Z Wagen, Regina H Reynolds, Jia Nee Foo, Aine Fairbrother-Browne, Emil K Gustavsson, Sarah Galgiano-Turin, Nicholas W Wood, Cornelis Blauwendraat, Sonia Gandhi, Mina Ryten
It is hypothesised that peripheral immune states responding to regional environmental triggers contribute to central neurodegeneration. Region-specific genetic selection pressures require this hypothesis to be assessed in an ancestry specific manner. Here we utilise genome-wide association studies and expression quantitative trait loci from African, East Asian and European ancestries to show that genes causing neurodegeneration are preferentially expressed in innate rather than adaptive immune cells, and that expression of these genes mediates the risk of neurodegenerative disease in monocytes in an ancestry-specific manner.
bioRxiv 2024.11.20.624489;
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The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1
Emil K. Gustavsson, Siddharth Sethi, Yujing Gao, Jonathan W. Brenton, Sonia García-Ruiz, David Zhang, Raquel Garza, Regina H. Reynolds, James R. Evans, Zhongbo Chen, Melissa Grant-Peters, Hannah Macpherson, Kylie Montgomery, Rhys Dore, Anna I. Wernick, Charles Arber, Selina Wray, Sonia Gandhi, Julian Esselborn, Cornelis Blauwendraat, Christopher H. Douse, Anita Adami, Diahann A.M. Atacho, Antonina Kouli, Annelies Quaegebeur, Roger A. Barker, Elisabet Englund, Frances Platt, Johan Jakobsson, Nicholas W. Wood, Henry Houlden, Harpreet Saini, Carla F. Bento, John Hardy, Mina Ryten
Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson's disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1. We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1. Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1. We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1. These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function—yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.
Science Advances; 26 Jun 2024; Vol 10, Issue 26
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The non-specific lethal complex regulates genes and pathways genetically linked to Parkinson's disease
Amy R Hicks, Regina H Reynolds, Benjamin O'Callaghan, Sonia García-Ruiz, Ana Luisa Gil-Martínez, Juan Botía, Hélène Plun-Favreau, Mina Ryten
Genetic variants conferring risks for Parkinson's disease have been highlighted through genome-wide association studies, yet exploration of their specific disease mechanisms is lacking. Two Parkinson's disease candidate genes, KAT8 and KANSL1, identified through genome-wide studies and a PINK1-mitophagy screen, encode part of the histone acetylating non-specific lethal complex. This complex localizes to the nucleus, where it plays a role in transcriptional activation, and to mitochondria, where it has been suggested to have a role in mitochondrial transcription. In this study, we sought to identify whether the non-specific lethal complex has potential regulatory relationships with other genes associated with Parkinson's disease in human brain.
Brain, Volume 146, Issue 12, December 2023, Pages 4974–4987
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Local genetic correlations exist among neurodegenerative and neuropsychiatric diseases
Regina H Reynolds, Aaron Z Wagen, Frida Lona-Durazo, Sonja W Scholz, Maryam Shoai, John Hardy, Sarah A Gagliano Taliun, Mina Ryten
Genetic correlation between traits can offer valuable insight into underlying shared biological mechanisms. Neurodegenerative diseases overlap neuropathologically and often manifest comorbid neuropsychiatric symptoms. However, global analyses show minimal genetic correlation among neurodegenerative and neuropsychiatric diseases. Importantly, local correlations can exist in the absence of global relationships. To investigate this possibility, we applied LAVA to genome-wide association studies of 3 neurodegenerative diseases (Alzheimer's disease, Lewy body dementia and Parkinson's disease) and 3 neuropsychiatric disorders (bipolar disorder, major depressive disorder and schizophrenia). We identified several local correlations missed in global analyses, including between all 3 neurodegenerative diseases and schizophrenia, and between Alzheimer's and Parkinson's disease. Collectively, we demonstrate that complex genetic relationships exist among neurodegenerative and neuropsychiatric diseases, highlighting putative pleiotropic genomic regions and genes with implications for common therapeutic targets.
NPJ Parkinson's Disease; 28 Apr 2023; Vol 9, Issue 1, Article 70
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Analysis of subcellular RNA fractions demonstrates significant genetic regulation of gene expression in human brain post-transcriptionally
Karishma D'Sa, Sebastian Guelfi, Jana Vandrovcova, Regina H Reynolds, David Zhang, John Hardy, Juan A Botía, Michael E Weale, Sarah A Gagliano Taliun, Kerrin S Small, Mina Ryten
Gaining insight into the genetic regulation of gene expression in human brain is key to the interpretation of genome-wide association studies for major neurological and neuropsychiatric diseases. Expression quantitative trait loci (eQTL) analyses have largely been used to achieve this, providing valuable insights into the genetic regulation of steady-state RNA in human brain, but not distinguishing between molecular processes regulating transcription and stability. Applying allele-specific expression analysis to genomic and transcriptomic data from paired nuclear and cytoplasmic fractions of human brain, we demonstrate that a significant proportion of genetic regulation of gene expression occurs post-transcriptionally in the cytoplasm, with genes undergoing this form of regulation more likely to be synaptic.
Scientific Reports; 24 Aug 2023; Vol 13, Issue 1, Article 13874
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Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia
Zhongbo Chen, Arianna Tucci, Mina Ryten
Correspondence reporting the identification of a deep intronic GAA repeat expansion in FGF14 as a cause of late-onset cerebellar ataxia, with implications for genetic testing strategies in this condition.
New England Journal of Medicine; 25 May 2023; Vol 388, Issue 21, e70
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Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia
Zhongbo Chen, Arianna Tucci, Valentina Cipriani, Emil K Gustavsson, Kristina Ibañez, Regina H Reynolds, David Zhang, Letizia Vestito, Alejandro Cisterna García, Siddharth Sethi, Jonathan W Brenton, Sonia García-Ruiz, Aine Fairbrother-Browne, Ana-Luisa Gil-Martinez, Genomics England Research Consortium, Nick Wood, John A Hardy, Damian Smedley, Henry Houlden, Juan Botía, Mina Ryten
Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing. This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights and strategies that raise the diagnostic yield.
Brain, Volume 146, Issue 7, July 2023, Pages 2869–2884
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IntroVerse: a comprehensive database of introns across human tissues
Sonia García-Ruiz, Emil K Gustavsson, David Zhang, Regina H Reynolds, Zhongbo Chen, Aine Fairbrother-Browne, Ana Luisa Gil-Martínez, Juan A Botia, Leonardo Collado-Torres, Mina Ryten
Dysregulation of RNA splicing contributes to both rare and complex diseases. RNA-sequencing data from human tissues has shown that this process can be inaccurate, resulting in the presence of novel introns detected at low frequency across samples and within an individual. To enable the full spectrum of intron use to be explored, we have developed IntroVerse, which offers an extensive catalogue on the splicing of 332,571 annotated introns and a linked set of 4,679,474 novel junctions covering 32,669 different genes. This dataset has been generated through the analysis of 17,510 human control RNA samples from 54 tissues provided by the Genotype-Tissue Expression Consortium.
Nucleic Acids Research, Volume 51, Issue D1, 6 January 2023, Pages D167–D178
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ggtranscript: an R package for the visualization and interpretation of transcript isoforms using ggplot2
Emil K Gustavsson, David Zhang, Regina H Reynolds, Sonia Garcia-Ruiz, Mina Ryten
The advent of long-read sequencing technologies has increased demand for the visualization and interpretation of transcripts. However, tools that perform such visualizations remain inflexible and lack the ability to easily identify differences between transcript structures. Here, we introduce ggtranscript, an R package that provides a fast and flexible method to visualize and compare transcripts. As a ggplot2 extension, ggtranscript inherits the functionality and familiarity of ggplot2 making it easy to use.
Bioinformatics, Volume 38, Issue 15, August 2022, Pages 3844–3846
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Leveraging omic features with F3UTER enables identification of unannotated 3'UTRs for synaptic genes
Siddharth Sethi, David Zhang, Sebastian Guelfi, Zhongbo Chen, Sonia Garcia-Ruiz, Emmanuel O. Olagbaju, Mina Ryten, Harpreet Saini & Juan A. Botia
There is growing evidence for the importance of 3' untranslated region (3'UTR) dependent regulatory processes. However, our current human 3'UTR catalogue is incomplete. Here, we develop a machine learning-based framework, leveraging both genomic and tissue-specific transcriptomic features to predict previously unannotated 3'UTRs. We identify unannotated 3'UTRs associated with 1,563 genes across 39 human tissues, with the greatest abundance found in the brain. These unannotated 3'UTRs are significantly enriched for RNA binding protein (RBP) motifs and exhibit high human lineage-specificity. We find that brain-specific unannotated 3'UTRs are enriched for the binding motifs of important neuronal RBPs such as TARDBP and RBFOX1, and their associated genes are involved in synaptic function.
Nature Communications volume 13, Article number: 2270 (2022)
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Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases
Rahel Feleke, Regina H Reynolds, Amy M Smith, Bension Tilley, Sarah A Gagliano Taliun, John Hardy, Paul M Matthews, Steve Gentleman, David R Owen, Michael R Johnson, Prashant K Srivastava, Mina Ryten
Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals to transcriptomically profile the LBDs. Using this approach, we found transcriptional alterations in multiple cell types across the LBDs, discovered evidence for widespread dysregulation of RNA splicing particularly in PDD and DLB, identified potential splicing factors coordinating this dysregulation, and identified transcriptomic commonalities and distinctions between the LBDs. These findings have important implications for the design of RNA-targeted therapies and highlight a potential molecular window of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.
Acta Neuropathologica; 26 Jul 2021; Vol 142, Issue 3, Pages 449–474
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Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
Zhongbo Chen, David Zhang, Regina H. Reynolds, Emil K. Gustavsson, Sonia García-Ruiz, Karishma D'Sa, Aine Fairbrother-Browne, Jana Vandrovcova, International Parkinson's Disease Genomics Consortium (IPDGC), John Hardy, Henry Houlden, Sarah A. Gagliano Taliun, Juan Botía & Mina Ryten
Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs, and find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event.
Nature Communications volume 12, Article number: 2076 (2021)
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Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease
Aine Fairbrother-Browne, Aminah T. Ali, Regina H. Reynolds, Sonia Garcia-Ruiz, David Zhang, Zhongbo Chen, Mina Ryten & Alan Hodgkinson
Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases. The mitochondrial genome encodes core respiratory chain proteins, but the vast majority of mitochondrial proteins are nuclear-encoded, making interactions between the two genomes vital for cell function. Here, we examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. We find strong regional patterns that are modulated by cell-type and reflect functional specialisation. Nuclear genes causally implicated in sporadic Parkinson's and Alzheimer's disease show much stronger relationships with the mitochondrial genome than expected by chance, and mitochondrial-nuclear relationships are highly perturbed in Alzheimer's disease cases.
Communications Biology volume 4, Article number: 1262 (2021)
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Detection of pathogenic splicing events from RNA-sequencing data using dasper
David Zhang, Regina H. Reynolds, Sonia Garcia-Ruiz, Emil K Gustavsson, Sid Sethi, Sara Aguti, Ines A. Barbosa, Jack J. Collier, Henry Houlden, Robert McFarland, Francesco Muntoni, Monika Oláhová, Joanna Poulton, Michael Simpson, Robert D.S. Pitceathly, Robert W. Taylor, Haiyan Zhou, Charu Deshpande, Juan A. Botia, Leonardo Collado-Torres, Mina Ryten
Although next-generation sequencing technologies have accelerated the discovery of novel gene-to-disease associations, many patients with suspected Mendelian diseases still leave the clinic without a genetic diagnosis. An estimated one third of these patients will have disorders caused by mutations impacting splicing. RNA-sequencing has been shown to be a promising diagnostic tool, however few methods have been developed to integrate RNA-sequencing data into the diagnostic pipeline. Here, we introduce dasper, an R/Bioconductor package that improves upon existing tools for detecting aberrant splicing by using machine learning to incorporate disruptions in exon-exon junction counts as well as coverage.
bioRxiv 2021.03.29.437534;
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Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information
Sebastian Guelfi, Karishma D'Sa, Juan A Botía, Jana Vandrovcova, Regina H Reynolds, David Zhang, Daniah Trabzuni, Leonardo Collado-Torres, Andrew Thomason, Pedro Quijada Leyton, Sarah A Gagliano Taliun, Mike A Nalls, International Parkinson's Disease Genomics Consortium, UK Brain Expression Consortium, Kerrin S Small, Colin Smith, Adaikalavan Ramasamy, John Hardy, Michael E Weale, Mina Ryten
Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease.
Nature Communications; 25 Feb 2020; Vol 11, Issue 1, Article 1041
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Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders
Niccolò E Mencacci, Regina Reynolds, Sonia Garcia Ruiz, Jana Vandrovcova, Paola Forabosco, Alvaro Sánchez-Ferrer, Viola Volpato, International Parkinson's Disease Genomics Consortium, UK Brain Expression Consortium, Michael E Weale, Kailash P Bhatia, Caleb Webber, John Hardy, Juan A Botía, Mina Ryten
Dystonia is a neurological disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures, often occurring in absence of any structural brain abnormality. Psychiatric comorbidities are frequent in patients with dystonia. Here we applied an unbiased systems-biology approach to explore the cellular specificity of all currently known dystonia-associated genes, predict their functional relationships, and test whether dystonia and neuropsychiatric disorders share a genetic relationship. Dystonia-associated genes were significantly enriched in adult nigral dopaminergic neurons and striatal medium spiny neurons, and co-expression modules enriched for dystonia genes showed significant enrichment of the heritability of major depressive disorder, obsessive-compulsive disorder and schizophrenia.
Brain; 1 Sep 2020; Vol 143, Issue 9, Pages 2771–2787
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Incomplete annotation has a disproportionate impact on our understanding of Mendelian and complex neurogenetic disorders
Zhang D, Guelfi S, Garcia-Ruiz S, Costa B, Reynolds RH, D'Sa K, Liu W, Courtin T, Peterson A, Jaffe AE, Hardy J, Botía JA, Collado-Torres L, Ryten M.
Growing evidence suggests that human gene annotation remains incomplete; however, it is unclear how this affects different tissues and our understanding of different disorders. Here, we detect previously unannotated transcription from Genotype-Tissue Expression RNA sequencing data across 41 human tissues. We connect this unannotated transcription to known genes, confirming that human gene annotation remains incomplete, even among well-studied genes including 63% of the Online Mendelian Inheritance in Man–morbid catalog and 317 neurodegeneration-associated genes. We find the greatest abundance of unannotated transcription in brain and genes highly expressed in brain are more likely to be reannotated.
Science Advances; 10 Jun 2020; Vol 6, Issue 24
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Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
Regina H Reynolds, Juan Botía, Mike A Nalls, International Parkinson's Disease Genomics Consortium (IPDGC), System Genomics of Parkinson's Disease (SGPD), John Hardy, Sarah A Gagliano Taliun, Mina Ryten
Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of alpha-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, suggesting that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.
NPJ Parkinson's Disease; 17 Apr 2019; Vol 5, Article 6
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