Speakers

Distinguished professor at Vilnius University, chief scientist/head of the department at the Institute of Biotechnology of Vilnius University and a chairman of the board of Life Science Center.

Prof. Virginijus Šikšnys currently holds a chair of distinguished professor at Vilnius University. He also serves as a chief scientist/head of the department at the Institute of Biotechnology of Vilnius University and a chairman of the board of Life Science Center. He is also a founder and chairman of the board of the “Caszyme” company. Prof. Virginijus Šikšnys’s research on the CRISPR-Cas has had a major impact in the field of gene editing. He together with co-authors, published seminal papers on Cas9 biochemistry that were the foundation for the translation of CRISPR-Cas bacterial immune system into a powerful genome-editing tool. He is a member of EMBO, EAM, Lithuania Academy of Sciences and Norwegian Academy of Sciences and letters. His work has been recently recognized with several awards and prizes including the Kavli Prize.

ABSTRACT

Title: New tools for genome editing: from CRISPR-Cas to transposon-associated proteins

In prokaryotes CRISPR-Cas system functions as an adaptive immune system that provides resistance against invading viruses. CRISPR-Cas nucleases Cas9 and Cas12 are routinely used for genome editing and are rapidly advancing into the clinics but there are still challenges to overcome. The first challenge is targeting space limitation due to the PAM requirement. I will show how systematic exploration of novel Cas9 orthologues that recognize different PAM sequences allowed us to expand targeting space [1]. Next, I will introduce you miniature nucleases that may help to overcome delivery problems using AAV vectors [2]. And finally, I will talk on the smallest genome editing tools (TnpB) that originate from transposons [3] and their relationship to CRISPR-Cas systems. 

  

Gasiunas G, et al. A catalogue of biochemically diverse CRISPR-Cas9 orthologs. Nat Commun. 2020 Nov 2;11(1):5512. 

Bigelyte G, et al. Miniature type V-F CRISPR-Cas nucleases enable targeted DNA modification in cells. Nat Commun. 2021;12(1):6191. 

Karvelis T, et al. Transposon-associated TnpB is a programmable RNA-guided DNA endonuclease. Nature. 2021; 599(7886):692-696. 

Sasnauskas G, et al. TnpB structure reveals minimal functional core of Cas12 nuclease family. Nature. 2023; 616(7956):384-389. 

Research leader, Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital

Associate professor, Lundbeck Foundation Center for GeoGenetics, GLOBE Institute, University of Copenhagen

Dr Buil is a computer scientist working in statistical genetics and genomics. He worked for 10 years at the Hospital de Sant Pau in Barcelona (Spain) as lead analyst of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. At the same time, he did a PhD in Statistical Genetics with the supervision of Dr. John Blangero from the Texas Biomedical Institute (San Antonio, Tx, USA). His dissertation demonstrates the practical utility of multivariate variance components methods on the study of the genetics of complex traits in family samples.

He then moved to the University of Geneva (Switzerland) as a postdoc at the Dermitzakis’ lab. There, he studied the genetic architecture of gene expression on different tissues and how to use gene expression as an intermediate phenotype with disease.

Currently he is a research leader at the Institute of Biological Psychiatry in Roskilde (Denmark) and associate professor at the University of Copenhagen. His main interest is answering questions of biological and medical importance by innovative analysis of large-scale datasets. His aim is to understand the etiology of mental disorders using different types of information by applying integrative approaches that recognize the importance of genetic and environmental factors and the interactions between them. The work in the Danish research environment offers him a unique opportunity to use large scale samples joining national register-based health data with national biobanks. In the last years, he has pioneered the development and application of quantitative genetics methods on Danish national registers by leveraging genealogical information.

ABSTRACT

Title of the talk: Leveraging national registers to study psychiatric genetics in Denmark 

Mental disorders such as schizophrenia, depression, autism or bipolar disorder are major contributors to the disease burden of our society. All of them are complex disorders with underlying genetic and environmental factors. While the past decade has provided insights into the genetics of psychiatric disorders, including advances in genetic variants discovery, risk prediction and treatment response prediction, we still face the challenge of achieving clinical utility, due in part to the existence of complex patterns of heterogeneity and clinical pleiotropy in psychiatric disorders. On the other hand, mental disorders present a high degree of comorbidity with different somatic diseases, including cardiovascular, metabolic and oncological diseases among others. The existing literature is however conflicting whereas the underlying mechanisms linking together mental illness and somatic diseases – genetic or non-genetic – remain unknown to a large extent.  

Here we present an approach to address relevant questions on the genetic architecture of mental disorders and in the genetic architecture underlying their comorbidity with somatic disorders by leveraging information from large national registers. We put together the medical records of millions of individuals with the genealogical information of the whole nation to perform classical quantitative genetic analyses that answer our questions of interest.  

In this talk I will present the general framework of the approach and will show some applied examples in the national Danish registers. The example will include a) the description of the whole Danish genealogy and its application to estimate heritabilities and genetic correlations among main grouped disorders as described in ICD10 chapters; b) the quantification of genetic and environmental factors affecting the observed comorbidity between mental disorders and cardiovascular diseases and c) the quantification of assortative mating for mental disorders and its implications on their prevalence and genetic architecture. Finally, I will explain the future directions of our research on the framework of using national registers to study psychiatric genetics in Denmark. 

VP of research, Muscular Dystrophy Association USA

Dr. Angela Lek is VP of research at the Muscular Dystrophy Association. She has extensive experience in elucidating the molecular mechanisms of neuromuscular diseases. Dr. Lek completed her PhD at the University of Sydney studying Limb Girdle Muscular Dystrophy, and her postdoctoral training at Boston Children’s Hospital and Harvard Medical School studying Facioscapulohumeral Dystrophy. She ran her own research program at Yale University for 3 years focusing on translational research before transitioning to her role at MDA. Her role now at MDA involves overseeing the award and management of research grant programs, venture philanthropy investments, and leading the scientific arm of MDA’s Kickstart program for ultra-rare gene therapy development. Dr. Lek consults for numerous gene therapy projects for neuromuscular diseases and is dedicated to facilitating the translation of promising research from bench to clinic. In addition to her day job, Angela is also a full-time carer for her husband who has been diagnosed with a neuromuscular disease and she is also passionate about patient advocacy and scientific communication to the patient community.

 

ABSTRACT

Title: Promises and challenges of translating genetic therapies for neuromuscular disorders

Genetic therapies delivered via adeno-associated viruses (AAVs) has proven to be a feasible strategy to treat the underlying genetic cause of numerous neuromuscular disorders (NMDs), capable of drastically altering disease progression. Muscular Dystrophy Association (MDA) has committed over $125M in gene therapies for NMDs over the past two decades, and our investment is now beginning to bear fruit in the form of approved therapies. Zolgensma for treatment of Spinal Muscular Atrophy has received regulatory approval in the US and EU, with imminent approval of microdystrophin gene therapies for Duchenne Muscular Dystrophy. Clinical trials for limb-girdle muscular dystrophies, congenital myopathies, Pompe disease, Danon disease, giant axonal neuropathy are underway, with many more programs in advanced preclinical stages. To continue our leadership role in this exciting field of medicine, MDA has made strategic investments to address logistical bottlenecks and remaining hurdles in the translation of genetic therapies for our patient population. This involves proactively engaging with key stakeholders in the field to implement initiatives ranging from clinical readiness and education at our clinic care centers, to advancing our internal gene therapy program catered to a selected ultra-rare disease in our Kickstart Program. This talk will discuss the issues at the forefront of translating gene therapy technology, with specific focus on MDA’s role in helping to shepherd in the new era of genetic medicines for NMDs.

FIMM-EMBL group leader, Institute for Molecular Medicine, University of Helsinki

Andrea is a FIMM-EMBL group leader at Institute for Molecular Medicine Finland (FIMM) and a research associate at Massachusetts General Hospital, Harvard Medical School. Andrea’s research interests lie at the intersection between epidemiology, genetics, and statistics. He leads a diverse group of 18 researchers including biologists, mathematicians, and medical doctors. He is a winner of an ERC starting grant and the Leena Peltonen Prize for Excellence in Human Genetics. He is co-leading two major international consortia: the COVID-19 host genetic initiative, the largest human genetic study of COVID-19, and the INTERVENE consortium, which aims to integrate AI and human genetics tools for disease prevention and diagnosis across biobanks in Europe. He has also initiated the FinRegistry project, one of the most comprehensive registry-based health studies in the world. His research vision is to integrate genetic data and electronic health records to enhance the early detection of common diseases and improve public health interventions.

 

ABSTRACT

Title: Can genetic associations for disease onset be used to predict disease prognosis? 

GWASs have extensively studied the genetics of disease incidence/onset. However, disease prognosis has been less studied, and it is less known if the genetic determinants of disease incidence overlap with those of disease prognosis and if existing polygenic score (PS) can be used to predict prognosis among diseased patients. We studied ten common diseases which are the leading cause of death in developed countries and defined diseases prognosis as the survival time between disease onset and death caused by the disease. We meta-analysed results from 5 biobanks for a total of N>1.5 million individuals and: 1. Examined association between PS for disease incidence and patients’ survival; 2. Carried out in-patient survival GWAS to uncover variants associated with disease prognosis; 3. Constructed theoretical framework to better understand our empirical results.

We show that PSs constructed from GWASs of disease incidence were weakly or no associated with patients’ prognostic outcomes. Moreover, prognosis GWASs, despite being the largest study so far for most diseases, did not uncover prognosis-specific signals and showed low heritability. By comparing to results from down-sampled incidence GWAS, we found that such lack of signals and heritability cannot simply be explained by the decreased sample sizes. We demonstrated through theoretical derivation and simulation how index event bias can lead to attenuated effects measured within the patient group. And we argue that genetic relationship between incidence and study-defined prognosis can be another factor impacting results in prognostic research. Overall, our results highlight the challenges in studying disease prognosis that the human genetic community will need to face in the upcoming years and serve as a starting point for subsequent development of clinically useful prognostic genetic scores.

Human Microbiome Research Program, University of Helsinki, Finland

Dr. Anne Salonen is a principal investigator and adjunct professor at University of Helsinki, Finland. She is also director of the Human Microbiome Research Program at the Medical Faculty, University of Helsinki. Dr. Salonen has multidisciplinary training in biosciences and PhD in microbiology (2004). Since 2007 she has been studying human microbiomes, contributing to the development and validation of methods for high-throughput microbiome analysis and to novel research concepts, such as the microbiota-based response stratification. Her current research is focused on the composition and activity of the intestinal microbiota in health and disease, especially in early life and in relation to interactions between diet, intestinal microbiota and health. Dr. Salonen is a co-principal investigator of the Finnish Health and Early Life Microbiota (HELMI) birth cohort and involved in maternal fecal microbiota transplantation studies in C-section infants.

Dr. Salonen’s research also entails female reproductive track micro- and mycobiota e.g. in relation to infertility and pregnancy complications and outcomes. Research methodology in Salonen laboratory ranges from NGS and other omics technologies to culture-based microbiology of anaerobes, including application and development of bioinformatic tools for microbiome research. More on our research at https://www.helsinki.fi/en/researchgroups/microbes-inside.

ABSTRACT

Title: Mother-infant microbiome interface in early development and reproduction 

All our mucosal surfaces are covered by a co-evolved microbial community, i.e. the microbiome (the microbiota and their genes) that can, depending on composition and function, either support normal physiological functions or promote disease. The gut microbiota has on organ-like fundamental role in human physiology, playing an important role in key functions such as digestion and drug metabolism as well as regulation of variety of immunological and metabolic processes. The vaginal microbiome protects the birth canal from infectious agents and regulates the mucosal immunity. Altered vaginal microbiota has been implicated in a number of gynecological and obstetric problems such as infertility and repeated miscarriages. Hence, microbiomes are an important source of phenotypic variation and plasticity, mediating and modifying associations between exposures and health outcomes.

The first bacteria populating the gut of naturally born infant come primarily from the mother. Many factors in modern life, such as birth by ceasarean section and antibiotic use can jeopardize the evolutionally conserved mother-infant microbiota transfer and subsequent colonization process, which is believed to contribute to the increased risk of immune-mediated diseases related to caesarean section birth and early antibiotic use.

The lecture will summarize recent results on the vaginal microbiome and especially its role on reproductive outcomes. I will discuss findings from our Finnish Health and Early life Microbiota birth cohort (N = 1055, PMID: 31253623), covering how perinatal factors and breast milk composition affect infant gut microbiota development, and how the developmental trajectories of the early gut microbiota associate to child health and well-being over the first 5 years of life. The patterns of vertical microbiota transfer from the parents to the child will be presented, both in natural and assisted settings, following maternal fecal microbiota transplant to C-section born neonates. The challenges and potential of different strategies to restore and modulate the maternal and early life microbiota to achieve health benefits are also discussed.

Professor, MD, PhD
Neuromuscular Research Center, University of Tampere
and Folkhälsan Institute of Genetics, Biomedicum, University of Helsinki

Born in Finland, Dr. Udd received his MD from the University of Berne, Switzerland in 1975, and completed residency training in neurology at the University Hospital in Umeå, Sweden, and the University Hospital in Helsinki, Finland. He received his PhD degree from Helsinki University in 1992 with the thesis on a new type of muscular dystrophy, causing the distal Tibial muscular dystrophy (TMD) in heterozygotes and severe LGMD2J in homozygote patients. With academic appointments (docent) at Tampere University from 1997 he became the head of the new program in 2004: Advanced Neuromuscular Diagnostics at the Tampere University Hospital, a nationwide and international quaternary referral center for neuromuscular disease patients with undetermined diagnosis. In 2008 he was appointed Professor of Neurology in Neuromuscular Disorders and the clinical service was upgraded in 2013: Neuromuscular Research Center, Tampere University Hospital. He is currently PI of one research group in Helsinki, at the Folkhälsan Research Center, and one group at Tampere University Hospital. Prof Udd is member of many international research boards in neuromuscular diseases. His research focuses on very rare neuromuscular diseases: clinical and molecular genetic research on muscular dystrophies, in particular: distal myopathies, rimmed vacuolar myopathies, limb-girdle dystrophies and myotonic dystrophy type 2. Since the first ever description of human muscle disease caused by titin mutations, TMD (Udd myopathy) and LGMD2J, the research efforts have resulted in more than 20 primary descriptions of new muscle diseases many with previously unknown myopathy genes.

 

ABSTRACT

Title: Multisystem proteinopathies MSPs – neurodegeneration, +/- muscle, +/- bone

 A new category of neurological genetic disorders consisting of motor neuron disease – ALS, ALS-Fronto Temporal Dementia, FTD alone, Rimmed vacuolar myopathies (RVM), Paget bone disease, Parkinsonism and all types of combinations of these diseases.

The MSP term first used 2010 for VCP-mutated IBMPFD (inclusion body myopathy with Paget and frontotemporal dementia) and is based on the defects in protein processing in post-mitotic tissues with altered protein quality control and/or autophagic removal of the defect proteins. Chaperones are responsible for protein quality control and thus heavily involved. The defects lead to abnormal accumulations (TDP-43, p62,…) in neurons and rimmed vacuoles in muscle. Ubiquitinated (misfolded) proteins are highly accumulated because they are not degraded due to insufficient autophagy. As these same accumulations are present in brain motor neurons, spinal motor neurons, frontotemporal neurons, and in the muscle tissue the term Multisystem proteinopathy MSP describes well the pathology. The same MSP pathology has later been identified with many other gene defects such as: HNRPA2B1, HNRPA1, TARDBP, MATR3, …. The presentation will deal with even more genes and phenotypes

Senior Researcher at the Norwegian Institute of Public Health

Ystrom’s main research interest is epidemiological studies of intergenerational transmission of risk for mental disorders. This includes extended pedigree and molecular genetic studies on passive genetic transmission and how heritable traits in parents have effect on children, or “genetic nurture”. Cross-disorder effects are rather the rule than the exception in intergenerational transmission of risk. His interests therefore span across common mental disorders, ADHD, normal personality, and substance use. He has conducted a number of pharmacoepidemiologic studies on psychotropic drugs and offspring psychological development using contrafactual designs. His research team integrates national health registries and large cohort studies with biobanks to apply designs for separating direct and indirect effects in epidemiological studies of children’s mental health and neurodevelopment.

His current research is directed towards estimating heterogeneity across neighborhoods and schools to evaluate how much genetic effects vary across geography and educational settings in a population. To do this he is the PI of the ERC Consolidator Project “GeoGen: The PsychoGeography of Intergenerational Mobility: Early life socioeconomic position, mental health, and educational performance” and a partner in the MSCA Doctoral Network “European Social Science Genetics Network (ESSGN). He is associate editor of JCPP Advances

 

ABSTRACT

Title:  Genes as environments – intergenerational transmission of mental health in the Norwegian Mother, Father and Child Cohort study.

The strongest predictor of a mental disorder in childhood and adolescence is to have a parent with a mental disorder. Associations between psychopathology in parents and children could be due to different modes of intergenerational transmission of risk, such as causal genetic variants shared among family members, risk environments shared among family members, or effect of parental psychopathology through the environment. Since adult mental health traits are heritable, parental effects on children through the environment also constitute indirect genetic effects. To understand intergenerational transmission, we have put parent-child associations through the prisms of extended children-of-twin designs, genetic trio analyses of polygenic scores, and trio-based genomic relatedness approaches. Using such triangulation, we have been able to evaluate the extent to which parents and children are similar in their mental health over and beyond what can be expected from genetic effects. What is more, we have been able to evaluate the impact of non-random mating on intergenerational transmission. In the same way that single genetic variants only explain a small proportion of total genetic effects, single measures of the environment usually contribute each to a small proportion of the total environmental factors for a trait. We believe parental mental health to only be a specific and small part of the total universe of parental indirect genetic effects (i.e. total effect of all parental heritable traits on child mental health through the environment). We have therefore developed a trio based genomic relatedness approach, Trio-GCTA, to estimate total maternal, parental, and child genetic effects on a measured trait in the family (e.g. child mental health). With this approach we can be agnostic to who is the index person for the trait, and indeed study dyadic or household measures. What is more, we can estimate the effect of heritable traits in genotyped siblings on an index child’s mental health. With this approach we have found indications for both positive and negative correlations between indirect and direct genetic effects, where a positive gene-environment correlation would inflate the SNP based heritability estimate, and a negative gene-environment correlation would deflate the heritability estimate.

Group Leader, Wellcome Sanger Institute, UK 

Emma Davenport is a Group Leader at the Wellcome Sanger Institute, Cambridge. Her group focuses on how genetics contributes to patient-to-patient variation in disease severity and response to treatment. In particular, they use gene expression data to identify subgroup specific signatures and to map expression quantitative trait loci (eQTLs) and their interactions.

Emma conducted her postdoctoral research in Professor Soumya Raychaudhuri’s lab at Brigham and Women’s Hospital, Harvard Medical School and the Broad Institute. There she developed a statistical framework to investigate how the administration of a drug alters the relationship between genomic variation and gene expression (drug eQTL interactions).

Emma completed her PhD research under the supervision of Professor Julian Knight at the University of Oxford. She investigated the genetic determinants of variation in the human response to common and rare infection, focusing on sepsis and common variable immunodeficiency disorders. A key finding was a gene expression signature stratifying patients into two distinct sepsis response signature (SRS) groups. The SRS1 group identifies individuals with an immunosuppressed phenotype and is associated with higher mortality.

ABSTRACT

Title: Using functional genomics to understand disease heterogeneity

Our research aims to understand how genetics contributes to the variation between patients in their disease severity and response to treatments. To understand this variation, we specifically focus on the regulation of gene expression in peripheral immune cells and diseases for which this is relevant such as sepsis and systemic lupus erythematosus (SLE). For both of these diseases, patients present with variable clinical features making diagnosis and treatment challenging.

We generate and analyse functional genomics datasets for large cohorts in order to identify gene expression signatures that stratify patients. We use expression quantitative trait locus (eQTL) mapping to identify the genetic drivers of this variation and improve our understanding of the molecular mechanisms underlying the disease. We are expanding our eQTL analysis into single cell transcriptomic data to provide further insights into the specific cell types in which a genetic variant is regulating gene expression.

Espen Molden is Research head at the Center for Psychopharmacology, Diakonhjemmet Hospital in Oslo, and Professor in Pharmacology at the University of Oslo (Norway). The Center for Psychopharmacology annually performs about 50.000 therapeutic drug concentration and genotyping of about 15.000 patients. These data along with biobanked samples comprise the basis for the research projects, which are mainly focused on pharmacokinetic and pharmacogenetic variability in relation to clinical response of psychiatric drugs, i.e., antidepressants and antipsychotics. This includes studies on gene/drug interactions, drug/drug interactions and drug/drug/gene interactions. Also performing studies on the identification of non-genetic biomarkers predicting variability in drug metabolism. Number of PubMed-indexed publications ~160. Overall goal of the research; to improve the precision of drug treatment of patients suffering of psychiatric diseases.

ABSTRACT

Title: The power of therapeutic drug monitoring data in pharmacogenomic studies.

Psychotropic drug treatments are associated with frequent ‘trial-and-error’ events reflecting insufficient clinical responses or serious side effects. In Norway, therapeutic drug monitoring (TDM) is frequently used as a tool for dose titration/adjustment to reach target serum concentrations. Our laboratory service annually analyses around 50.000 TDM samples, providing a huge number of patients with metabolizer phenotypes of psychiatric drugs stored in our database. Many of the patients have also been genotyped at our laboratory for variant alleles relevant for metabolic activity of cytochrome P450 (CYP) enzymes. By linking TDM and genotype data, we can perform studies precisely estimating the quantitative effects of genotypes on drug concentrations and metabolizer phenotypes with high statistical power. Furthermore, we can follow the patients TDM profiles over time and determine events of drug switching, which could be linked to genotypes and provide data on potential treatment failure in relation to pharmacogenomics. Finally, TDM phenotypes can be used for discovery of new genetic variants important for variability in drug metabolism and other pharmacokinetic processes, e.g., by genome-wide association studies.

Associate professor, University of Copenhagen 

Ida Moltke is an associate professor at the Department of Biology, University of Copenhagen. She has an MSc in Bioinformatics and PhD in population genetics and statistical genetics both from the University of Copenhagen. After finishing her PhD, she was postdoc at the Department of Human Genetics at the University of Chicago for 3 years and then moved back to Copenhagen to start her own research group in 2015.

Her research consists of developing and applying computational methods to analyse genetic data with the goal of answering questions about human evolution, history and disease. Among many other things, she has worked on numerous genetic studies focused on Greenlanders to gain insights into their population history, how they have adapted to the cold environment and what genetic variants cause them to get diseases.

ABSTRACT

Title: An example of how valuable disease studies in historically small and isolated populations can be

For a long time, the standard in human disease genetics has been to focus on large European and Asian populations. In this talk I will argue based on population genetics that it can be extremely valuable to study other populations as well, especially historically small and isolated populations, like the Greenlandic population. To illustrate how valuable, I will present several genetic variants that we have identified in the Greenlandic population over the past few years. Almost all of these variants have a large population level impact on health-related complex traits, like type 2 diabetes, BMI and lipid levels. For instance, we have identified a single loss-of-function variant with an allele frequency of 0.17 in Greenland and a recessive OR for type 2 diabetes of 10.3 (p=1.6´10^-24). I will also briefly address how the identification of these variants can potentially lead to personalized medicine in Greenland.

Professor, PharmD PhD

Jesse Swen is a full professor of clinical pharmacy, in particular translational pharmacogenetics. He works as a clinical pharmacist-clinical pharmacologist at the Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center where he is the chair of the laboratory of the hospital pharmacy.

The long-term central goal of his career is to improve the outcomes of drug treatment by gaining a better understanding of the genetic mechanisms that result in inter-individual variability in drug response. To this end, he is working on the following research topics:

• Dissecting the impact of rare, structural, and regulatory variants on drug absorption, distribution, metabolism, and excretion (ADME)
• Elucidating the mismatch between the drug metabolizer genotype and the capacity of an individual to metabolize drugs (phenoconversion).
• Translating pharmacogenomics to patient care.

This work is seamlessly integrated with his work as chair of the pharmacy laboratory. He has (co-) authored more than 150 (Web of Science indexed) articles in international peer reviewed scientific journals and several chapters in books. He is one of the primary investigators of the “Ubiquitous Pharmacogenomics” project (www.upgx.eu) and leader of the PREPARE trial that assessed the clinical utility of pharmacogenetics panel testing across 7 European sites. In addition, he is an active member of the Dutch Pharmacogenetics Working Group (DPWG) and the US Clinical Pharmacogenetics Implementation Consortium (CPIC).

 

ABSTRACT

Title: Implementing pharmacogenomics panel testing in Europe: results from the U-PGx PREPARE study

Retrospective, prospective, and naturalistic studies all provide compelling evidence that genetic variation affects the way people respond to drugs. For several indications, such as DPYD testing in oncology, pharmacogenetics testing is now routinely applied in clinical practice. Moreover, specific recommendations on how to tailor drug treatment based on genetic test results are available from the Dutch Pharmacogenetics Working Group (DPWG) and Clinical Pharmacogenetics Implementation Consortium (CPIC) for a large number of drugs. In addition to pre-prescription testing for a single gene, pharmacogenetic panel-based testing represents a new model for precision medicine. While several small studies indicate a panel approach is indeed favourable, convincing clinical evidence is lacking. The Ubiquitous Pharmacogenomics Consortium recently completed the PREemptive Pharmacogenomic testing for prevention of Adverse drug Reactions (PREPARE) study. In this presentation, the results of the PREPARE study that investigated the clinical impact of a pre-emptive genotyping approach of a panel of PGx variants covering 12 important pharmacogenes combined with the guidelines of the Dutch Pharmacogenetics Working Group in almost 7000 patients will be presented.

PhD, postdoctoral fellow at Prof. Kim Jensen lab, The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Copenhagen, Denmark

Kadi Lõhmussaar is a postsdoctoral researcher at Prof. Kim Jensen’s lab at the NNF Center for Stem Cell Medicine (reNEW) in Copenhagen, Denmark. She obtained her BSc and MSc degrees in the Genetechnology and Biomedicine programme, respectively, at the University of Tartu (Estonia). Her Master’s thesis work was performed at the lab of Dr. Viljar Jaks focusing on stem cell signaling networks and liver regeneration. After finishing her MSc studies, she joined the world-leading stem cell research lab led by Prof. Hans Clevers in the Hubrecht Institute (The Netherlands) to perform a 9-month Erasmus post- graduate internship working on the establishment of ovarian cancer organoid models. The great research and motivating environment encouraged her to continue the project at the Clevers’ lab, being enrolled as a PhD student in July, 2016. During the doctorate studies, she stayed focused on gynecological cancer modeling, extending her interest also beyond ovarian cancer research to cervical tissue. She defended her PhD thesis in November 2020, after which she relocated to Copenhagen for postdoctoral research.

ABSTRACT

Title: Adult stem cell-derived 3D organoids in modelling tissues in health and disease.

The last decade has witnessed rapid advancements in different in vitro tissue culturing technologies. In particular, adult stem cell-based 3D organoid technology, first described by Prof. Clevers and colleagues in 2009, has become one of the superior models in studying various epithelial tissues in health and disease. During my presentation, I will touch upon the historical timeline and the current status of this cutting-edge technology, including the discussion on the advantages and limitations of the organoid models up to date. I will bring examples from my own work with ovarian and cervical cancer organoids to illustrate the promise the technology holds for the future.

Professor, Division of Psychiatry, University College London; UCL Genetics Institute, Genes Evolution and Environment, University College London; Genomics England 

Karoline is Professor of Genetic Epidemiology at University College London where she leads the “Diversity in Genetics” group. Her research focusses on the genetic and environmental risk factors for diseases by leveraging the unique characteristics of diverse populations. She has developed methodological standards for diverse samples as well as innovative methods to empower locus discovery and to assess transferability of genetic risk factors. She is also the Scientific Lead for Diverse Data at Genomics England which aims to reduce health inequalities and improve patient outcomes within genomic medicine.

 

ABSTRACT

Title: Genomic medicine for ancestrally diverse populations

Since the publication of the first human genome sequence two decades ago, millions of genomes have been sequenced or genotyped. However, the vast majority were European ancestry samples. Despite repeated calls for change, representation of diverse populations has not improved over the last years.

We used different data resources from the UK to assess whether the existing findings from European ancestry samples are transferable to other groups and explore the impact of ancestry and population for downstream applications of genomics including genetic risk prediction, causal inference, genetic diagnoses, and genetically informed cancer treatment.

Genes and Health (G&H) is a community based, long-term study in British Bangladeshi and British Pakistani people. We used data from 23K participants to characterize the genetic architecture of cardiometabolic traits. We found evidence for transferability for the vast majority of cardiometabolic loci that were sufficiently powered to replicate in G&H: the PAT ratios were all >0.8 for the risk factor traits, but only 0.62 for CAD. The relative accuracy of PGS compared to European ancestry was high for some traits, including HDL-C, but lower for CAD and MD.

Using data from the 100,000 Genomes Project, we assessed variant tiering amongst rare disease patients with different ancestry. Compared to the European ancestry group, we found that significantly more variants were prioritised in most other ancestry groups. This difference was largely driven by tier 2 and 3 variants, implying higher rates of variants of uncertain significance. We identify insufficiently large reference allele frequencies for diverse ancestry groups as a likely cause.

In conclusion, it is important to establish the transferability of existing findings from genetic and genomic research across diverse ancestry groups. We identify areas that need improvement to ensure equitable genomic medicine, in particular genetic prediction of diseases risk and variants of uncertain significance in rare disease diagnostics.

Professor

Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Denmark, BGI-Research, Shenzhen, China, and Institute of Metagenomics, Qingdao-Europe Advanced Institute for Life Sciences, Qingdao, China

Karsten Kristiansen is Professor of Molecular Biology and heads the Laboratory of Genomics and Molecular Biomedicine at the Department of Biology, University of Copenhagen. He is also Professor and Director at BGI-Research, Shenzhen, China and the Institute of Metagenomics, Qingdao-Europe Advanced Institute for Life Sciences, Qingdao, China. After graduation from the University of Copenhagen, he held research positions at the Max-Planck-Institut für Molekulare Genetik in Berlin and at the Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild, in Paris. He was full professor and head of Department of Molecular Biology, later Department of Biochemistry and Molecular Biology, University of Southern Denmark, 1992-2008, before he was recruited as professor and Head of the Department of Biology, University of Copenhagen in 2008. Since 2015 he has shared his time between University of Copenhagen and his institutes in Qingdao and Shenzhen, China. Central themes of the research of Professor Kristiansen concern the interaction between the host genome, the host immune system and the gut microbiota in regulating gut health and energy metabolism, and how interaction between different nutrients modulates energy homeostasis. In addition, his research groups now explore the interaction between the gut microbiota and the brain. Recently, he has initiated work to isolate communities of soil-borne bacteria to be used as bio-pesticides. For these projects, his research groups use a combination of molecular biology approaches, animal and plant studies, metagenomics and genomics. He has published more than 400 articles in refereed journals, many of which in high-ranking journals such as Science, Nature, and Cell, and he is a WoS Clarivate highly cited researcher.

 

ABSTRACT

Title: The microbiota – Everything Everywhere All at Once

Monogenic diseases offer clear insight into the relation between the genome and diseases, but the importance of the host genome in relation to more complex multifactorial diseases has proven more difficult to establish. During the last decades it has become well established that commensal bacteria extensively colonize external as well as internal surfaces of the human body and play important roles in relation to metabolism and immune functions. Furthermore, evidence has been presented that the gut microbiota may also affect behavior. However, the exact molecular mechanisms by which bacteria in exert their actions remain elusive. In this lecture, I will summarize recent work from Copenhagen, Shenzhen, and Qingdao demonstrating how distinct changes in the gut and oral microbiota are associated several multifactorial diseases, with a focus on metabolism, and how we now by using multi-omics approaches are able to establish causality. I will conclude the lecture by summarizing our recent work linking the gut microbiota to schizophrenia and bipolar depression.

Professor, MD, PhD
Department of Clinical Pharmacology
University of Helsinki

 

ABSTRACT

Title: Pharmacogenetics of lipid-lowering therapy

Assistant professor, University Medical Center Groningen, University of Groningen, Department of Genetics, Groningen, the Netherlands 

Since 2021, Monique van der Wijst is an assistant professor in the department of Genetics at the University Medical Center Groningen, the Netherlands. There she studies how genetics impacts gene expression, its regulation, and the immune response. To facilitate this, she has founded the single-cell eQTLGen consortium, an international, collaborative effort aimed at identifying the genetic variants that regulate expression and its regulation taking advantage of single-cell population-based datasets. Additionally, she has been setting up various single-cell (scRNA-seq, multiomics, spatial) and high-throughput experimental (CRISPR-coupled single-cell sequencing, MPRA) read-outs in the lab. She believes it is the combination of large-scale population-based single-cell QTL meta-analyses coupled to high-throughput experimental approaches that will allow functional interrogation of the consequences of genetic variation and cell-to-cell heterogeneity. Ultimately, she expects this information will provide us with the personalized and disease-relevant context of gene regulation and as such can aid in the realization of personalized medicine in the future.

 

ABSTRACT

Title: Single-cell consortium for federated PBMC data pipeline for cell-type-specific eQTL mapping and downstream analyses 

Over the last decade, single-cell RNA sequencing (scRNA-seq) has grown in popularity as a potentential alternative to bulk RNA-seq, as scale, cost and sensitivity have significantly improved. These developments have now paved the way for the generation of large numbers of population-based scRNA-seq datasets that are a valuable resource for studying the effect of genetic variation (through expression quantitative trait locus (eQTL) mapping) on expression of individual cell types. To fully leverage these emerging data resources, we have founded the single-cell eQTLGen consortium (sc-eQTLGen), aimed at pinpointing the cellular contexts in which disease-causing genetic variants affect gene expression.

For this purpose, we have developed a pipeline that harmonizes the preprocessing, QC, cell type annotation and eQTL mapping of peripheral blood mononuclear cell (PBMC) scRNA-seq data. Every cohort in the consortium has run this pipeline, and only the non-privacy sensitive summary statistics were shared and combined in a federated manner.

Here, we present the results of the first data freeze in which we have meta-analyzed scRNA-seq-derived eQTL summary statistics of over 2,000 individuals for each of the major cell types in PBMCs. These results revealed the cell types in which the eQTLs manifest themselves.

Upcoming data freezes will further increase the sample size, cell type resolution, and number of donor characteristics under study, and will expand our analyses to other data modalities. Thereby, we expect that the sc-eQTLGen framework enables us and the community to gain a more complete understanding of gene expression and its regulation in health and disease.

Department of Genetics, Yale School of Medicine

Monkol received his PhD at the University of Sydney under the mentorship of Kathryn North. He then travelled to Boston to do his post-doc with Daniel MacArthur at Massachusetts General Hospital and the Broad Institute. His post-doctoral work focused on generating the largest collection of human protein coding variants called the ExAC project. The resource has been used by the rare disease community to better interpret rare variants observed in disease causing genes. He also was involved in many collaborations aimed at improving the diagnosis rate of neuromuscular diseases, which led to several novel disease gene discoveries. He started his lab in Yale in 2018 with a continual focus on improving diagnosis rate and developing novel genetic therapies.

 

ABSTRACT

Title: High throughput functional assays to improve interpretation of rare variants discovered in neuromuscular disease genes

The rapidly increasing list of variants of uncertain significance (VUS) discovered in individuals and our inability to interpret clinical consequences of these rare variants is an unappreciated challenge in the diagnosis of rare diseases.

Dystroglycanopathies are caused by mutations in enzymes involved in the glycosylation of alpha-dystroglycan (alpha-DG). The underlying pathogenic variants are typically ultra-rare with many unique to affected families. We developed an adaptable workflow called SMuRF (Saturation Mutagenesis-Reinforced Functional assays). We then employed the IIH6C4 antibody that binds to glycosylated alpha-DG coupled with SMuRF to screen variants in enzymes associated with dystroglycanopathy. We used the genes, FKRP and LARGE1 as proof concept and generated functional scores for more than 99.5% of all possible single nucleotide variants (SNVs).

SMuRF scores correlate well with clinical reports, showing its potential to aid classification of variants that remained to be definitively classified. SMuRF revealed that missense variants tend to be more disruptive in the catalytic domain than in the stem domain of FKRP. Similarly, SMuRF scores demonstrated that missense variants tend to be most disruptive in the XylT domain, which is critical for enzymatic activity in LARGE1. The successful application of SMuRF demonstrates it is feasible to quantify the effect of variants on enzymatic activity.

Professor at Department of Cell and Molecular Biology, Karolinska Institutet, Sweden 

Rickard Sandberg is Professor in Molecular Genetics at the Karolinska Institutet, leading a research group studying transcriptional dynamics and regulation using novel single-cell methods. The lab pioneered the development of single-cell RNA-sequencing (incl. the Smart-seq methods) and has continuously developed single-cell technologies at the absolute forefront. Using single-cell methods, the lab mapped out the patterns of allelic expression in single cells, culminating in the transcriptome-wide inference of transcriptional bursting kinetics and its genomic encoding. Rickard received his PhD from Karolinska Institute in 2004, thereafter pursued a postdoc with Christopher Burge at MIT working on post-transcriptional gene regulation. In 2008, he obtained funding to start his own lab at Karolinska Institutet and later the Ludwig Institute for Cancer Research. He became an EMBO Young Investigator (2012), a Vallee Scholar (2015) and received Nordic prizes including Jahres Prize for younger researchers (2014) and Göran Gustaffson prize in molecular biology (2018). In 2015, he became a full Professor at the Karolinska Institute and in 2019 he was elected member of EMBO and the Nobel Assembly at the Karolinska Institute.

 

ABSTRACT

Title: Novel strategies to study transcriptional dynamics and alternative splicing in single cells

Single-cell methods are currently broadly used to map cell types and genetic programs, although often at the expense of only sequencing ends of RNA molecules. My lab has been developing single-cell RNA-sequencing methods that sequence from the full length of the RNA molecules in cells, and this has been instrumental in developing novel strategies to map transcriptional dynamics, allelic expression and increasingly splicing regulation from single cells. I will present how to obtain scalable scRNA-seq with similar cost and throughput as commercial droplet-based methods while capturing more RNAs and providing full-length coverage. Using these techniques, we are exploring the temporal dynamics of expression at allelic resolution to answer often debated questions on co-expression of neighbouring genes in the genome, and the genomic encoding of transcriptional bursting kinetics. Moreover, we have developed improved strategies for mapping alternative splicing regulation across cell types from single-cell data, and in the mouse brain, we reveal an unappreciated wealth of splicing regulation.

Associate Professor, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet

Sara Hägg, PhD, is Associate Professor in Molecular Epidemiology at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet in Stockholm, Sweden. She leads a research group that focuses on epidemiological studies of aging, with a special interest in biological aging mechanisms and the association with age-related traits such as frailty and dementia. She has also participated in many large-scale genome-wide association studies and used genetic data to leverage the Mendelian Randomization method for providing evidence on causality in aging studies. She currently leads several projects with a focus on age-associated diseases, e.g., Alzheimer´s disease, Covid-19 and Cancer, with funding from the National Institutes of Health, the Swedish Research Council and the Swedish Cancer Society.

 

ABSTRACT

Title: Human genetic studies of aging and their implications for precision health

Today, the population of the world is getting older but evolution has not prepared us well for the demographic change. There is no positive selection for aging after reproduction. Twin and family-based studies have concluded that heritability of longevity is 15-30%, although it has been suggested that this is an overestimation due to assortative mating. Thus, large genome-wide association studies (GWAS) of longevity and parental life-span have been modest in their discovery of genetic loci.

Lately, many biomarkers useful for tracking biological aging across the lifespan have been identified. The most established ones are the so-called epigenetic clocks, which are summarized weighted scores of DNA methylation levels at CpG sites across the genome. The heritability of epigenetic clocks has been estimated to be 30-50% with the most recent GWAS on 40,000 individuals identifying more than 130 genetic loci. Another biomarker of aging is telomere length, which has a heritability of 35-80%, and the latest GWAS using UK Biobank data found about 200 loci. Hence, it seems that genetic predisposition to processes underlying biological aging may still be important for late-life health. In the presentation, I will discuss further how this information may be useful for studies in precision health.

Prof, PhD, Department of Biotechnology and Biomedicine, Technical University of Denmark, Denmark

Susanne Brix is Professor in Immune-Microbiota Interactions at the Department of Biotechnology and Biomedicine, Technical University of Denmark since 2018. She holds an MSc in Biotechnology from the Technical University of Denmark and a PhD in Nutritional Immunology from 2005, during which she worked at the Nestlé Research Centre in Lausanne, Switzerland. She has since 2014 been heading the Disease Systems Immunology group at the Technical University of Denmark. She is an elected member of the Danish Academy of Natural Sciences, a council member for The Independent Research Fond Denmark, and serves in several national and international steering committees, including the Million Microbiomes of Human Project (MMHP). Since 2021, she holds the FII institute Research Chair of DTU in Immune-based Prediction of Disease.

 

ABSTRACT

Title: Early life host-microbiota interactions and later disease development

Multiple factors including parental genetics, delivery mode, older siblings, and feeding regimen during early life are known risk modifiers for development of non-communicable diseases throughout life. Less attention has been focused on if and how these factors may change the early microbiota composition and derived metabolites, thereby affecting immune programming and later disease risk. Here, using longitudinal and quantitative profiling of functional microbial changes in infants and young children, we have identified early gut bacterial-derived metabolites that are influenced by above risk factors, regulate mucosal antibody production, as well as resistome dynamics in the gut during early life, and influence later disease trajectories.

Tiffany Morris is a Market Development manager at Illumina based in the UK. She has been at Illumina for 5 years focussed on Pharmacogenomics and other preventative genomics applications. Her presentation today is focussed on Illumina’s recent advancements to whole genome sequencing including long read sequencing.