Abstract of the talk
The study of the microbial gut community, the gut microbiome, has received much attention due to its role in human health. However, disproportionately most studies have focused on populations that are Westernised; Westernisation being a process that has been driven by industrialisation culminating in dietary and lifestyle changes. In a large-scale meta-analysis combining newly sequenced non-Westernised cohorts and publicly available datasets I will discuss the impact Westernisation has had on the gut microbiome of healthy individuals. With recent advances in metagenomic analyses I will show that the true level of microbial diversity in the gut has been underestimated. That Westernisation has caused a reduction in overall microbial diversity and many potentially important intestinal species, such as the enigmatic Prevotella copri complex have become less prevalent. Utilising ancient microbial fossils, I will show that the microbiomes of contemporary non-Westernised populations are akin to those of our ancestors. Overall, revealing the impact of Westernisation has been dramatic and rapid in the alteration of our long-standing host co-evolved microbiome.
Alastair graduated from Barts and the London (QMUL) in 2007 and he pursued integrated training via the Foundation Academic Programme and an NIHR Academic Clinical Fellowship at UCL. Between 2012-2016 he undertook a PhD in Neuroscience at UCL and between 2014-2016 he undertook an MSc in Epidemiology at London School of Hygiene and Tropical Medicine. Alastair re-joined QMUL and the PNU in 2017 to lead the Parkinson’s programme of work.
His research interests are Parkinson’s disease and other neurodegenerative disorders, particularly early identification and epidemiological aspects, including environmental, clinical and genetic determinants. He is the co-principal investigator of the PREDICT-PD study and principal investigator for the East London Parkinson’s Disease project. He is a member of the International Parkinson and Movement Disorder Society (MDS) and he graduated from the MDS LEAP leadership programme in 2020. He sits on the MDS Epidemiology Study Group and the MDS Prodromal Parkinson’s Subcommittee. He also sits on the steering committee of the Global Parkinson’s Genetics Program (GP2) and leads one of the working groups, focusing on Training and Networking. He is the Chair of the Think Brain Health Global initiative.
Abstract of the talk
Determinants of Parkinson’s disease – genes, environment and interactions
This talk will begin with a discussion the apparent rising global burden of Parkinson’s disease (PD). I will summarise what we know about the genetic basis of PD and also what we know about environmental risk factors. I will talk about how midlife comorbidities may contribute to PD risk and progression. I will then explore the dichotomy of genetic versus environmental risk factors for PD, and how one can tell us about the other, and what evidence exists for interactions between them. I will finish by talking about future perspectives and ongoing projects.
She has two masters’ degrees, first one in biochemistry/pharmacology from the University of Sciences and Technologies and the second one in immunology from Pierre & Marie Curie Institute. Anne Puel has PhD degree in immunology from Pierre & Marie Curie Institute. In addition, from the Paris Descartes University she has Habilitation à diriger des recherches. Anne has supervised 16 postdoctoral fellows, 13 PhD and 27 MSc students, and 5 laboratory engineers.
Her main research concerns Immunology, Immunity, Chronic mucocutaneous candidiasis, Mutation and Interferon. Her study looks at the relationship between Immunology and topics such as Receptor, which overlap with Tumor necrosis factor alpha. The concepts of her Immunity study are interwoven with issues in Immunodeficiency, Pneumonia, Virology, Asymptomatic and Allele. Her biological study deals with issues like Phenocopy, which deal with fields such as Immunoglobulin G, Disease and Autoantibody.
Abstract of the talk
Human genetic and immunological host factors in critical COVID-19 pneumonia
Most individuals, following infection with SARS-CoV-2 will be asymptomatic or develop a benign infection. However, approximately 10% of the infected cases will develop hypoxemic COVID-19 pneumonia, leading to critical disease in around 3% of cases. The resultant risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. The molecular and immunological host factors of critical COVID-19 pneumonia will be discussed, in particular, inborn errors of type I interferons (IFNs), found 1-5% of patients with critical pneumonia and neutralizing auto-antibodies against IFN-α, IFN-β and/or IFN-ω, found in approximately 15-20% of patients with critical pneumonia.
Abstract of the talk
Exploring the interplay between germline genetic variation and responses to cancer immunotherapy and chronic viral infection across a large patient cohort
We have characterised variation in the longitudinal peripheral immune response to anti-PD1 checkpoint immunotherapy given to treat melanoma in a cohort of >250 patients using both transcriptomics (cell-specific bulk RNAseq, adaptive immune receptor sequencing and single-cell RNAseq) and immunological methods (high-throughput flow-cytometry). By integrating these data with long-term clinical outcomes, we are able to identify a number of peripheral immune features that show association with long-term complete responses to treatment, as well as predisposition to autoimmune toxicity in the pre-treatment state. Interestingly, we find germline genetic variation interacts with both having cancer, as well as response to immunotherapy to modulate gene expression – allowing us to identify eQTL specific to these states, as well as chronic viral infection (CMV). I will demonstrate the identification of one such cancer-specific eQTL that is associated with B cell expression of the key lymphopoietic cytokine IL7, carriage of which regulates the pan-cellular responses to anti-PD1 treatment and predisposes to treatment related autoimmune toxicity.
Abstract of the talk
Using genetics to unravel the heterogeneity of depression
The burden on society by depression is undisputable. This large burden is partly due to a course pattern that is more chronic than often assumed, and the large heterogeneity of depression contributes to non-response to our standardly available treatments. Using data from the Netherlands Study of Depression and Anxiety (NESDA, www.nesda), Penninx will illustrate both points. NESDA has followed >3000 adults, including many patients with depression and/or anxiety disorders, over 13 years of follow-up. When looking at its long-term course, especially when also considering the transitions into other affective disorders over time, it has been found that chronicity is more the rule than the exception (Verduijn et al. BMC Med 2017). Taking heterogeneity of depression into account could lead to precision psychiatry approaches that help reduce depression’s chronicity. Using NESDA data, Penninx’s team has consistently found that immuno-metabolic dysregulations vary as a function of depression heterogeneity: dysregulations map more consistently to “atypical” neurovegetative symptoms reflecting altered energy intake/expenditure balance (hyperphagia, weight gain, hypersomnia, fatigue and leaden paralysis). Such findings are confirmed when utilizing with genetic data, including genome-wide gene expression as well as DNA available in NESDA as well as in larger general population based studies (e.g. UK Biobank). Some preliminary treatment studies further suggest that the presence of immuno-metabolic dysregulations in depressed persons may moderate antidepressant effects of standard or novel (immunomodulatory) interventions. So, an immuno-metabolic depression dimension could dissect depression’s heterogeneity and potentially match depressed subgroups to treatments with higher likelihood of clinical success. Overall, NESDA findings also point out the relevance of dissecting the heterogenous group of depressed persons so that personalized medicine strategies could contribute to reducing the chronic nature and disease burden of depression.
Abstract of the talk
From associations to clinical utility: impact of functional CYP2C19 and CYP2D6 gene variants on treatment in patients with depression: a Danish cohort study
Convincing evidence of the utility of pharmacogenetic (PGx) testing in clinical practice is still limited. Here we present population-based findings of the associations of CYP2D6 and -2C19 variants with antidepressant treatment outcomes, including switching, emergency department contacts, and suicide attempt or self-harm in young people with depression.
We studied all individuals born in Denmark between 1981 and 2006 (N=17,297) diagnosed with depression at a psychiatric hospital and using selected antidepressants. Using array-based single-nucleotide-polymorphism genotype data, the CYP2D6 and -2C19 genotypes of these individuals were translated into metabolizer phenotypes categorized into CYP2C19/CYP2D6 normal (NM, reference group), ultra-rapid- (UM), rapid- (RM), intermediate- (IM), or poor-metabolizer (PM) status according to the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium. We followed all individuals from their first prescription of es-/citalopram, sertraline and fluoxetine until the occurrence of a treatment outcome within 1-year applying Poisson regression analysis adjusted for confounders, including sex and age and co-medication and comorbidity.
Children with CYP2C19 PM status using (es)citalopram had increased risks of switching (Incidence Rate Ratio (IRR) 1.64 [95% confidence interval (CI): 1.10-2.43]), and of suicide attempt or self-harm (IRR 2.67 [95% CI; 1.57-4.52]). Young adults with CYP2C19 PM status (19-25 years) using sertraline had an increased risk of switching (IRR 2.06 [95% CI; 1.03-4.11]). Young adults with CYP2D6 PM status using fluoxetine had an increased risk of emergency department contacts (IRR 3.28 [95% CI; 1.11-9.63]). No statistically significant associations were detected in adults aged 26 to 37 years, potentially due to low power. In conclusion, CYP2C19 and CYP2D6 PM phenotypes were associated with outcomes of treatment with antidepressants in children and younger adults with depression indicating the benefit from PGx testing for PGx guided treatment at younger ages.
Abstract of the talk
From molecules to health records: utility of omics at population scale
Application of different omic technologies is now feasible at population scale. This talk will present examples of how the integration of different omics in large patient and population studies can help to predict disease risk, understand mechanisms, and reveal shared connections between different diseases.
Abstract of the talk
Toxicogenomics and IATA for the development of new chemicals drugs, and materials: the FHAIVE experience
Toxicology is undergoing through profound changes as the focus of investigation is shifted from the observation of apical phenomena to mechanistic aspects of the exposure. If on one hand we need to ensure that dangerous chemicals do not emerge, on the other, we also need to promote rapid and sustainable innovation to successfully overcome the modern challenges of humankind. Toxicogenomics aims at clarifying the mechanism of action (MOA) of chemicals by using omics assays. The Adverse Outcome Pathways (AOP) concept is also emerging to contextualise toxicogenomics-derived MOA. Efforts are ongoing to anchor AOPs to molecular assays, but systematic embedding of AOP-derived in vitro tests and Integrated Approaches to Testing and Assessment (IATA) are still unestablished. At the same time, toxicogenomics-based evidence still struggles to gain regulatory acceptance. At the Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), we develop new IATA (Integrated Approaches for Testing and Assessment) based on big data science, artificial intelligence (AI), network science, toxicogenomics, molecular assays and cell technology via an integrated and comprehensive knowledge graph approach. In this talk, I will present some examples of the advances we are implementing in the field of toxicology and how they can be used in a unified framework to guide the safe-, sustainable- and effective-by-design chemicals, drugs, and materials.
Abstract of the talk
PRECISE4Q
Stroke is one of the most severe medical problems with far-reaching public health and socio-economic impact, gathering momentum in an ageing society. PRECISE4Q set out to minimise the burden of stroke for the individual and for society. Over the course of the last 4 years we developed multi-dimensional data-driven predictive models enabling – for the first time – personalised stroke treatment, addressing patient’s needs in four stages: prevention, acute treatment, rehabilitation and reintegration.
Abstract of the talk
A spatial multi-omics atlas of the human lung reveals a novel gland-associated immune niche
To better understand lung function and immunity, we have generated a multi-omics single cell, nuclei and Visium Spatial Transcriptomics data set for 5 proximal-to-distal locations of the human lung. Our atlas defines novel cell types/states which we map back into the macro- and micro-anatomical tissue context, including distinct pericyte and smooth muscle subtypes, immune-recruiting fibroblasts, peribronchial and perichondrial fibroblasts, peripheral nerve associated fibroblasts, Schwann cells and submucosal gland (SMG) duct cells. Using our atlas we define a survival niche for IgA-secreting plasma cells at the SMG, comprising the newly defined epithelial SMG-Duct cells, along with SMG-Serous cells and B and T lineage immune cells. We propose a signalling circuit that establishes and supports this niche. Our online resource for data browsing, automated cell type annotation and spatial mapping of genes will facilitate the study of tissue microenvironments such as the newly defined gland-associated immune niche (GAIN).
Ewan completed his PhD at the Wellcome Sanger Institute with Richard Durbin. In 2000, he became Head of Nucleotide data at EMBL-EBI and in 2012 he took on the role of Associate Director at the institute. He became Director of EMBL-EBI in 2015. Ewan led the analysis of the Human Genome gene set, mouse and chicken genomes and the ENCODE project, focusing on non-coding elements of the human genome. Ewan’s main areas of research include functional genomics, DNA algorithms, statistical methods to analyse genomic information (in particular information associated with individual differences in humans and Medaka fish) and use of images for chromatin structure.
Ewan is a non-executive Director of Genomics England, and a consultant and advisor to a number of companies, including Oxford Nanopore Technologies and Dovetail Genomics. Ewan was elected an EMBO member in 2012, a Fellow of the Royal Society in 2014 and a Fellow of the Academy of Medical Sciences in 2015.
He has received a number of awards including the 2003 Francis Crick Award from the Royal Society, the 2005 Overton Prize from the International Society for Computational Biology and the 2005 Benjamin Franklin Award for contributions in Open Source Bioinformatics. On December 29, Ewan Birney was made a Commander of the British Empire (CBE) as part of the Queen’s New Year’s Honours List for 2019. Ewan received the honour in recognition of his services to computational genomics and leadership across the life sciences.
Abstract of the talk
Molecular biology is now a leading example of a data intensive science, with both pragmatic and theoretical challenges being raised by data volumes and dimensionality of the data. These changes are present in both “large scale” consortia science and small scale science, and across now a broad range of applications – from human health, through to agriculture and ecosystems. All of molecular life science is feeling this effect.
This shift in modality is creating a wealth of new opportunities and has some accompanying challenges. In particular there is a continued need for a robust information infrastructure for molecular biology. This ranges from the physical aspects of dealing with data volume through to the more statistically challenging aspects of interpreting it. A particular problem is finding causal relationships in the high level of correlative data. Genetic data are particular useful in resolving these issues.
The pandemic has brought together operational public health delivery (eg, testing and DNA sequencing of the infectious agent) alongside research and models. The rate of learning has increased between these two domains and delivered better and better products for both policy makers and research. I will illustrate this with examples including the expansion of the Alpha and Delta SARS-CoV-2 genomes and integrating genomic and contact tracing work.
Abstract of the talk
Challenges and prospects in ancient metagenomcis
For years the field of ancient DNA was dominated by human ancient DNA studies. More recently, the study of ancient metagenomes has started to provide fascinating, millennial-scale insights into the evolution of particular pathogens and changes in the composition and function of entire microbial communities or microbiomes. However, the analysis of ancient metagenomes is challenging as, just like human DNA, the DNA of interest is usually degraded and, depending on the sample type, present in low abundance. One of the biggest challenges facing ancient metagenome studies is the presence of modern contamination – both in terms of postdepositional contamination of samples and the presence of contamination in modern reference genomes – which can result in false positive identifications. In this talk, I will discuss some of the pitfalls and technical challenges related to working with ancient metagenomes, drawing on various case studies from ancient chewing gums to parasites, and discussing some of the methods we and others have developed to address them.
Abstract of the talk
This presentation aims to:
- highlight key findings from our past register-based research on ADHD across the lifespan
- show preliminary findings from new Horizon 2020 research program (TIMESPAN) that aims to advance the management of individuals with ADHD and co-occurring cardiometabolic disease
- discuss challenges and opportunities with register-based research.
Abstract of the talk
The influence of population admixtures on the evolution of complex human traits: insights from genomic, phenotypic and functional data
The peopling of Eurasia has been characterised by complex demographic history, including hybridization with archaic hominins and subsequent population movements and admixture. The spread of anatomically modern humans into new environments has been facilitated by a series of adaptations in complex traits but the interplay between dietary, immunological, behavioural and other environmental factors and population movements and contacts in shaping these evolutionary processes is poorly understood. To address this issue, we have leveraged genomic and phenotypic data from population-level biobanks with analysis of DNA from ancient humans and archaic hominins to investigate how genetic variation from ancient human and archaic hominin populations shaped evolution of phenotypic variation in complex human traits. For donors to the Estonian biobank, we found substantial differences in ancestry and evidence of strong recent natural selection for several anthropometric (including height, body mass index and pigmentation of eye and hair), metabolic (blood pressure, heart rate and cholesterol levels), reproductive and sleep-related traits. Furthermore, analysis of Neandertal DNA present in donors to European and East Asian biobanks show population-specific associations with autoimmunity, cancers and type 2 diabetes and long-range regulatory effects on patterns of transcription factor activation in the human genome. These results show the importance of past population contacts and gene flow for the evolution of complex human traits.
Abstract of the talk
Emerging computational approaches in population studies of the human microbiome
Microbial communities have been recognized as essential components of our physiology and health. Understanding their role in health and well-being is challenging due to the high temporal and spatial variation in the presence and abundances of microbial strains both within and between individuals. Together with carefully designed intervention studies, the accumulation of population-level research data has opened up new possibilities for understanding individuality against the context of population-level variation. Taking advantage of the current and emerging data resources from complex microbial ecosystems relies on our ability to develop efficient and reliable computational approaches. This talk highlights recent advances in statistics, machine learning, and data science methodology in human microbiome research, with a particular emphasis on integrating microbiome data with other, complementary information sources, modeling temporal and spatial variation, and anticipating long-term disease risk in large populations.
Abstract of the talk
Studying rare variants at the population level: How EHR-linked biobanks give us new insight into monogenic disease
Much of what we know about monogenic disease is based on studies of individuals and their families. Large biobanks that link genetic variants to dense phenotypic information allow us to study these diseases at the population level, leading to new insights into the phenotypic manifestations of genetic disease and the variants that cause them. This talk will focus on methods that enable us to study genetic variants at the population level, give examples of common pitfalls of EHR-based phenotyping, and show how biobanks can be used to derive clinically relevant knowledge that has the potential to help patients.
Michael originally trained as a pharmacologist and subsequently studied Human Molecular Genetics at Imperial College before undertaking his PhD at St George’s University of London. His doctoral research was focused on the resolution of the genetic basis of recessive disorders present at elevated frequency in Old Order Amish populations. In 2009 Michael moved to King’s College London where his research capitalised on advances in DNA sequencing technologies to identify the genetic basis of a series of rare diseases that had proved intractable to traditional gene mapping approaches.
Between 2014 and 2021 Michael was head of Human Genetics at Genomics plc overseeing the development of the technology platform for target discovery and polygenic risk profiling. He continues to be actively involved in developing the analytical approaches needed to deploy contemporary genomic technologies at scale in healthcare systems and is currently head of Research and Innovation for the South East England NHS Genomic Medicine Service Alliance.
Abstract of the talk
Driving discovery in inflammatory skin disease with human genetics
The association of genetic variation with disease phenotypes provides a robust scientific platform to identify causal biological processes. Our recent large-scale studies have defined the genetic variation that explains a substantial proportion of the genetic risk of inflammatory skin disease and formed the substrate to identify the molecular mechanisms of disease, the cell-types in which they occur and the optimal targets for intervention.
Our genetic studies have supported the development of new therapies, targeting TYK2 and IL36, and defined genetic variation that influences therapeutic response in psoriasis. We have also established the causal role of specific molecular processes in the development of acne, identified putative therapeutic targets and demonstrated the relationship between genetic risk and disease severity.
Abstract of the talk
A multidisciplinary approach to better understand treatment resistant depression
Major depressive disorder (MDD) is a common psychiatric disorder and a leading cause of disability worldwide. Although current treatments are generally effective, up to one-third of individuals with MDD fail to respond to first line therapies, and are typically referred to as having treatment-resistant depression (TRD). TRD patients have higher rates of mortality, higher health care costs, and are hospitalized longer compared to those with MDD who are treatment responsive. There is considerable motivation to provide more effective care for patients with TRD. Despite its overall burden and clinical importance, studying TRD has been challenging due to unstandardized definitions of TRD and difficulty in ascertaining large samples of these severe cases. These major challenges have largely limited our understanding of its aetiology.
I propose to use a multidisciplinary approach covering epidemiology, genetic epidemiology, gene mapping, and machine learning to systematically investigate TRD. Leveraging powerful resources of the national registries and biobank data, we have a unique opportunity to investigate the genetic and non-genetic factors underlying TRD, and integrate these factors in prediction models aiming to detect TRD early in patients’ treatment history. These steps are essential for achieving the translational goal of enabling personalized therapeutic approach in this disorder, thereby to reduce morbidity, mortality, and suffering in patients with TRD.
Abstract of the talk
Search for new molecules to cure Parkinson’s disease
Parkinson’s disease (PD) affects about10 million people and no treatment exists that can slow down or stop the disease progression. In PD midbrain dopamine (DA) neurons degenerate and die causing in addition to major motor symptoms also non-motor symptoms. Current drugs can only temporarily alleviate the motor symptoms, but non-motor symptoms remain untreated. Our group has discovered an endoplasmic reticulum (ER) located protein with neurotrophic factor (NTF) activities – cerebral dopamine neurotrophic factors (CDNF). We have solved the three-dimensional structure of CDNF and shown that their structure and mode of action radically differs from other known NTFs. CDNF can protect and repair midbrain DA neurons in rodent and non-human primate neurotoxin models of PD at least as efficiently as other known NTFs. However, differently from other NTFs, CDNF is located in the ER, where they regulate ER stress and unfolded protein response pathways. CDNF knockout (KO) mice develop an age-dependent loss of enteric neurons resulting in pathological changes of gastrointestinal function. The deficiencies of CDNF KO mice are similar to those seen in early stages of Parkinson’s disease. Herantis Pharma Plc. has tested CDNF in phase I-II clinical trials in PD patients and CDNF achieved its primary endpoint of safety and tolerability. Moreover, significant increases in DAT PET signaling and improved UPDRS scores were observed in some, but not all, CDNF-treated patients. Since CDNF cannot pass through the blood – brain barrier (BBB), it is delivered directly into the patient’s brain via catheters that are installed during invasive surgery. We have recently discovered a fragment of CDNF (ngCDNF) that can pass through the BBB after subcutaneous administration. Use of ngCDNF may allow peripheral delivery avoiding intracranial surgery. Considering that CDNF protein doesn’t have optimal properties as a drug, we discovered small compounds which mimic the action of CDNF & its homologous protein MANF. Preliminary data indicate that these compounds regulate ER stress and protect cultured DA neurons from 6-hydroxydopamine induced death.
Abstract of the talk
The human microbiome represents a complex ecosystem which, through its emergent properties, contributes essential functions to its host. Using integrated multi-omics in combination with high-throughput experimental systems, we are now starting to unravel these functions in the context of human health and disease. These insights will pave the way for revolutionary prognostic, diagnostic and therapeutic approaches.
Abstract of the talk
Polygenic risk score for Parkinson’s disease and probability of substantia nigra hyperechogenicity in “healthy” adults
Several studies have investigated the association of the PD PRS with several aspects of well-established PD. By means of transcranial sonography (TCS), a larger area of increased echogenicity (hyperechogenicity) in substantia nigra (SN) has been found in patients with different neurodegenerative diseases, especially in PD compared to controls. This SN+ is thought to reflect increased iron deposits. Although its exact meaning remains unknown, it has been proposed to be a marker of SN degeneration or vulnerability. We sought to evaluate the association of PRS with the SN+in normal population who have high and low Parkinson’s disease PRS. An influential role for polygenic inheritance in PD is strongly supported by a number of studies, that revealed a significant association between disease risk, age of onset, motor progression, and cognitive decline with PRS, calculated from GWAS summary statistics for PD.However, all studies published today, examined the association of PRS with several aspects of well-established PD. There are no studies that investigate the association of this score with the probability of SN+ and its risk markers.
Abstract of the talk
m6A RNA modifications, splicing and cancer
Splicing efficiency varies among transcripts, and tight control of splicing kinetics is crucial for coordinated gene expression. N-6-methyladenosine (m6A) is the most abundant RNA modification and is involved in regulation of RNA biogenesis and function.
In our work we show that early m6A deposition specifies the fate of transcripts regarding splicing kinetics and alternative splicing. m6A deposition near splice junctions promotes fast splicing, while m6A modifications in introns are associated with long, slowly processed introns and alternative splicing events.
Several components of the molecular machinery regulating m6A deposition and removal have been shown to be involved in cancer. We have studied m6A methylation events in breast cancer cells using Direct RNA Sequencing that are directly affecting splicing and molecular function in disease to understand the molecular mechanism of m6A in cancer and to evaluate the potential of m6A-mediated mis-splicing as a therapeutic target in cancer.
