Lasse Folkersen

NucleusGenomics | mynucleus.com

DNA variation analysis has become indispensable in many aspects of modern biomedicine, most prominently in the comparison of normal and tumor samples. Thousands of samples are collected in local sequencing efforts and public databases requiring highly scalable, portable, and automated workflows for streamlined processing. Here, we present nf-core/s...

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis,...

Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation and is mediated by multiple immune cell types. In this work, we aimed to determine the relevance of changes in cell proportions in peripheral blood mononuclear cells (PBMCs) during the development of disease and following treatment. Samples from healthy blood...

Background Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but failure of satisfying treatment response occurs in a significant proportion of patients. Here we present a longitudinal multi-omics study aimed at detecting molecular and cellular processes in peripheral blood associated with a successful methotrexate treat...

Circulating proteins play key roles in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 15,150 participants. We identified 180 pQTLs, of which 50 were...

Background: Fibroblast growth factor 23 (FGF-23) is associated with a range of cardiovascular and non-cardiovascular diseases in conventional epidemiological studies, but substantial residual confounding may exist. Mendelian randomization approaches can help control for such confounding. Methods: SCALLOP consortium data on 19,195 participants were...

Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum’s dense dopaminergic innervation. Here, we performed a comprehensive analysis of the genetic and...

The number of people accessing their own polygenic risk scores (PRSs) online is rapidly increasing, yet little is known about why people are doing this, how they react to the information, and what they do with it. We conducted a qualitative interview-based study with people who pursued PRSs through Impute.me, to explore their motivations for seekin...

The number of people accessing their own polygenic risk scores (PRSs) online is rapidly increasing, yet little is known about why people are doing this, how they react to the information, and what they do with it. We conducted a qualitative interview-based study with people who pursued PRSs through Impute.me, to explore their motivations for seekin...

Fibroblast growth factor 23 (FGF-23) is associated with a range of cardiovascular and non-cardiovascular diseases in conventional epidemiological studies, but substantial residual confounding may exist. Mendelian randomisation approaches can help control for such confounding. SCALLOP consortium data on 19,195 participants were used to generate an F...

Objective: Neonatal lupus erythematosus (NLE) may develop after transplacental transfer of maternal autoantibodies with cardiac manifestations (congenital heart block, CHB) including atrioventricular block, atrial and ventricular arrhythmias, and cardiomyopathies. The association with anti-Ro/SSA antibodies is well established, but a recurrence ra...

Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation and is mediated by multiple immune cell types. In this work we aimed to determine the relevance of changes in cell proportions in peripheral blood mononuclear cells (PBMCs) during development of disease and during treatment. Methods Samples from hea...

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, enters human cells using the angiotensin-converting enzyme 2 (ACE2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, play...

Background and aims Genome-wide association studies (GWAS) identified a coronary artery disease (CAD) risk locus on 13.q34 tagged by rs61969072 (T/G). This variant lies in an intergenic region, proximal to ING1, CARKD and CARS2 but its causal relationship to CAD is unknown. Methods and Results We first demonstrated that rs61969072 and tightly link...

(The American Journal of Human Genetics 109, 12–23; January 6, 2022) An unfortunate corruption of two equations on page 14 appeared in the version of this paper published on January 6. It has been corrected here and online. The publisher apologizes for this error. New formula used in LDpred2 We also slightly modify the formula used in Privé et al.;...

The low portability of polygenic scores (PGSs) across global populations is a major concern that must be addressed before PGSs can be used for everyone in the clinic. Indeed, prediction accuracy has been shown to decay as a function of the genetic distance between the training and test cohorts. However, such cohorts differ not only in their genetic...

There is growing interest in the clinical application of polygenic scores as their predictive utility increases for a range of health-related phenotypes. However, providing polygenic score predictions on the absolute scale is an important step for their safe interpretation. We have developed a method to convert polygenic scores to the absolute scal...

A promise of genomics in precision medicine is to provide individualized genetic risk predictions. Polygenic risk scores (PRS), computed by aggregating effects from many genomic variants, have been developed as a useful tool in complex disease research. However, the application of PRS as a tool for predicting an individual’s disease susceptibility...

We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL ov...

We sought to explore individuals’ motivations for using their direct-to-consumer genetic testing data to generate polygenic risk scores (PRSs) using a not-for-profit third-party tool, and to assess understanding of, and reaction to their results. Using a cross-sectional design, users of Impute.me who had already accessed PRS results were invited to...

Background : The mechanisms underlying rupture of a coronary atherosclerotic plaque and development of myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI) remain unresolved. Increased arginase 1 activity leads to reduced nitric oxide (NO) production and increased formation of reactive oxygen species due to uncouplin...

Objectives Advances in immunotherapy by blocking TNF have remarkably improved treatment outcomes for rheumatoid arthritis patients. Although treatment specifically targets TNF, the downstream mechanisms of immune suppression are not completely understood. The aim of this study was to detect biomarkers and expression signatures of treatment response...

The predictive utility of polygenic scores is increasing, and many polygenic scoring methods are available, but it is unclear which method performs best. This study evaluates the predictive utility of polygenic scoring methods within a reference-standardized framework, which uses a common set of variants and reference-based estimates of linkage dis...

Background: There is growing interest in the clinical application of polygenic scores as their predictive utility increases for a range of health-related phenotypes. However, providing polygenic score predictions on the absolute scale is an important step for their safe interpretation. Currently, polygenic scores can only be converted to the absolu...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quant...

Background Integration of functional genomic annotations when estimating polygenic risk scores (PRS) can provide insight into aetiology and improve risk prediction. This study explores the predictive utility of gene expression risk scores (GeRS), calculated using imputed gene expression and transcriptome-wide association study (TWAS) results. Meth...

The low portability of polygenic scores (PGS) across global populations is a major concern that must be addressed before PGS can be used for everyone in the clinic. Indeed, prediction accuracy has been shown to decay as a function of the genetic distance between the training and test cohorts. However, such cohorts differ not only in their genetic d...

Background Integration of functional genomic annotations when estimating polygenic risk scores (PRS) can provide insight into aetiology and improve risk prediction. This study explores the predictive utility of gene expression risk scores (GeRS), calculated using imputed gene expression and transcriptome-wide association study (TWAS) results. Meth...

DNA-damaging cancer therapies induce interferon expression and stimulate the immune system, promoting therapy responses. The immune-activating STING (Stimulator of Interferon Genes) pathway is induced when DNA or double-stranded RNA (dsRNA) is detected in the cell cytoplasm, which can be caused by viral infection or by DNA damage following chemo- o...

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, th...

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each pr...

Background Advances in immunotherapy by blocking TNF have remarkably improved treatment outcomes for rheumatoid arthritis (RA) patients. Although treatment specifically targets TNF-α, the downstream mechanisms of immune suppression are not completely understood, and the reason for the reduced efficacy in a significant fraction of patients remains u...

Objectives Advances in immunotherapy by blocking TNF have remarkably improved treatment outcomes for rheumatoid arthritis patients. Although treatment specifically targets TNF, the downstream mechanisms of immune suppression are not completely understood. The present study was aimed to detect biomarkers and expression signatures of treatment respon...

The background of this mini-study is that many users want to upload DNA-sequencing data from Dante-labs to impute.me. As more and more vendors offer sequencing data, this is expected to become more and more frequent, also from other vendors (e.g. Nebula genomics etc). This data type is different than the data type obtainable from microarray samples...

Background The predictive utility of polygenic scores is increasing, and many polygenic scoring methods are available, but it is unclear which method performs best. This study evaluates the predictive utility of polygenic scoring methods within a reference-standardized framework, which uses a common set of variants and reference-based estimates of...

To date, interpretation of genomic information has focused on single variants conferring disease risk, but most disorders of major public concern have a polygenic architecture. Polygenic risk scores (PRSs) give a single measure of disease liability by summarizing disease risk across hundreds of thousands of genetic variants. They can be calculated...

Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whe...

A video animation showing how to read DNA-code from a spit sample using microarray

Aims Small conductance Ca²⁺-activated K⁺ channels (SK channels, KCa2) are a new target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of KCa2 channels that is currently in clinical development for treatment of AF. The aim of this study is to present the electrophysiological profile and mechanism of action of AP3066...

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. By mapping and replicating protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, we identified 467 pQTLs for 85 proteins. The pQTLs...

The purpose of this mini-study is to find the fastest and most accurate implementation for a full polygenic risk score (PRS) calculator. The scope is that PRS-weights already are in place. Then four specific plink-based implementations are defined. Each will be checked for concordance with other methods, prediction rate and speed. Full code is docu...

To date, interpretation of genomic information has focused on single variants conferring disease risk, but most disorders of major public concern have a polygenic architecture. Polygenic risk scores (PRS) give a single measure of disease liability by summarising disease risk across hundreds of thousands of genetic variants. They can be calculated i...

Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whe...

Background: Despite extensive research in atherosclerosis, the mechanisms of coronary atherothrombosis in ST-elevation myocardial infarction (STEMI) patients are undetermined. Objectives: Our aim was to find candidate genes involved in STEMI by analysing leucocyte gene expression in STEMI patients, without the influence of secondary inflammation...

Background The mechanisms underlying rupture of a coronary atherosclerotic plaque and development of myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI) remain unknown. Increased arginase-1 activity leads to reduced nitric oxide production and increased formation of reactive oxygen species due to uncoupling of the e...

NK cells are innate lymphocytes that play an integral role in tumor rejection and viral clearance. Unlike their other lymphocyte counterparts, NK cells have the unique ability to recognize and lyse target cells without prior exposure. However, there are no known NK cell-specific genes that are exclusively expressed by all NK cells. Therefore, ident...

Background Of the 108 Schizophrenia (SZ) risk-loci discovered through genome-wide association studies (GWAS), 96 are not altering the sequence of any protein. Evidence linking non-coding risk-SNPs and genes may be established using expression quantitative trait loci (eQTL). However, other approaches such allelic expression quantitative trait loci (...

Background and aims: Calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-β-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of HPSE is controversial in osteogenesis and bone remodeling while it is unexplored in vascular c...

In this review, current trends in personal genetics are covered. The main differences between the "classic" rare high-effect mutations vs the combined effects of thousands of common, low-risk variants are outlined, and then we provide examples of possible clinical use of microarray-based genetic measurements of rare high-risk mutations, and diagnos...

Identifying the causes of similarities and differences in genetic disease prevalence among humans is central to understanding disease etiology. While present-day humans are not strongly differentiated, vast amounts of genomic data now make it possible to study subtle patterns of genetic variation. This allows us to trace our genomic history thousan...

Background: Genetic variant landscape of coronary artery disease is dominated by noncoding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct genes both to gain insights into perturbed functions and better assess the risk of dis...

Are you considering to test your own DNA? Do you want to learn more about your health and ancestry? Understand your DNA — A Guide is about what you can use genetics for. For a few hundred dollars, you can now scan your own genes. Millions of people all over the world have already done so. Everyone wants to see what they can get to know about themse...

Genetic variant landscape of cardiovascular disease (CVD) is dominated by non-coding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct gene both to gain insights into perturbed functions and better assess the risk of disease. In...

Limb girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic myopathies leading primarily to proximal muscle weakness. It is caused by mutations at over 50 known genetic loci typically from mutations in genes encoding constituents of the sarcolemmal dystrophin complex or related functions. Herein we describe the case of two sibling...

Objective In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor. Here, we investigated whether non-HLA single nucleotide polymorphisms (SNP), conferring low disease risk on their own, interact w...

Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chr...

In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope alleles (SE), is the highest genetic risk factor. Here, we aimed to investigate whether gene-gene interactions influence this HLA-DRB1 related major disease risk; specifically, we set out to test if...

Aortic valve stenosis (AS) is the most common valvular heart disease, characterized by a thickened and calcified valve causing left ventricular outflow obstruction. Severe AS is a significant cause of morbidity and mortality, affecting approximately 5% of those over 70 years of age 1,2,3 . Little is known about the genetics of AS, although recently...