Søren Brunak

University of Copenhagen · Center for Protein Research

Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated wit...

The host genetics of SARS-CoV-2 has previously been studied based on cases from the earlier waves of the pandemic in 2020 and 2021, identifying 51 genomic loci associated with infection and/or severity. SARS-CoV-2 has shown rapid sequence evolution increasing transmissibility, particularly for Omicron variants, which raises the question whether thi...

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several wi...

Environmental and genetic risk factors contribute to the development of borderline personality disorder (BPD). We conducted the largest GWAS of BPD to date, meta-analyzing data from 12,339 cases and 1,041,717 controls of European ancestry, and identified six independent associated genomic loci. Gene-based analysis identified nine risk genes. We obs...

Discovery of cancer risk variants in the sequence of the germline genome can shed light on carcinogenesis. Here we describe gene burden association analyses, aggregating rare missense and loss of function variants, at 22 cancer sites, including 130,991 cancer cases and 733,486 controls from Iceland, Norway and the United Kingdom. We identified four...

Motivation Despite lifestyle factors (LSFs) being increasingly acknowledged in shaping individual health trajectories, particularly in chronic diseases, they have still not been systematically described in the biomedical literature. This is in part because no named entity recognition (NER) system exists, which can comprehensively detect all types o...

Background The initial evaluation of coronary stenosis during coronary angiography is typically performed by visual assessment. The visual assessment of coronary angiographies has limited accuracy compared to quantitative methods like fractional flow reserve and quantitative coronary angiography. Quantitative methods are also more time-consuming an...

Objective To determine the association between human leukocyte antigen (HLA) alleles and migraine, migraine subtypes, and sex‐specific factors. Background It has long been hypothesized that inflammation contributes to migraine pathophysiology. This study examined the association between migraine and alleles in the HLA system, a key player in immun...

There is a limited understanding of risk factors and comorbidities in trigeminal neuralgia, a disease characterized by paroxysms of severe unilateral facial pain and a higher incidence in women. We aim to identify temporally associated comorbidities involving trigeminal neuralgia by analyzing nationwide disease trajectories. Using data from 7.2 mil...

Aims/hypothesis Type 2 diabetes is a chronic condition that is caused by hyperglycaemia. Our aim was to characterise the metabolomics to find their association with the glycaemic spectrum and find a causal relationship between metabolites and type 2 diabetes. Methods As part of the Innovative Medicines Initiative - Diabetes Research on Patient Str...

Background: Centralized collection and processing of healthcare data across national borders pose significant challenges, including privacy concerns, data heterogeneity and legal barriers. To address some of these challenges, we formed an interdisciplinary consortium to develop a feder-ated health data network, comprised of six institutions across...

Importance Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited. Objective To investigate the genetics of APs and affiliated arrhythmias. Design, Setting, and Participants This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases ( ICD )...

Lifestyle factors (LSFs) are increasingly recognized as instrumental in both the development and control of diseases. Despite their importance, there is a lack of methods to extract relations between LSFs and diseases from the literature, a step necessary to consolidate the currently available knowledge into a structured form. As simple co-occurren...

Quantifying the contribution of genetics and environmental effects on disease initiation and progression, as well as the shared genetics of different diseases, is vital for the understanding of the disease etiology of multimorbidities. In this study, we leverage nationwide Danish registries to provide a granular atlas of the genetic origin of disea...

Electronic health records can be used to track diagnoses and drug prescriptions in large heterogeneous populations over time. Coupled with recent advances in causal inference from observational data, these records offer new opportunities to emulate clinical trials and identify potential targets for drug repositioning. Here, we run a hypothesis gene...

Disease trajectories, defined as sequential, directional disease associations, have become an intense research field driven by the availability of electronic population-wide healthcare data and sufficient computational power. Here, we provide an overview of disease trajectory studies with a focus on European work, including ontologies used as well...

Aims/hypothesis Metabolic risk factors and plasma biomarkers for diabetes have previously been shown to change prior to a clinical diabetes diagnosis. However, these markers only cover a small subset of molecular biomarkers linked to the disease. In this study, we aimed to profile a more comprehensive set of molecular biomarkers and explore their t...

Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severe impact on maternal–fetal health. We identified five genetic loci linked to PPH in a meta-analysis. Functional annotation analysi...

SignalP (https://services.healthtech.dtu.dk/services/SignalP-6.0/) is a very popular prediction method for signal peptides, the intrinsic signals that make proteins secretory. The SignalP web server has existed since 1995 and is now in its sixth major version. In this historical account, we (three authors who have taken part in the entire journey p...

Aims: Heterogeneity in the rate of β-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease-modifying clinical trials. Integrative analyses of baseline multi-omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rat...

Motivation Despite lifestyle factors (LSFs) being increasingly acknowledged in shaping individual health trajectories, particularly in chronic diseases, they have still not been systematically described in the biomedical literature. This is in part because no named entity recognition (NER) system exists, which can comprehensively detect all types o...

Decision-making in healthcare relies on the ability to understand patients' past and current health state to predict, and ultimately change, their future course. Artificial intelligence (AI) methods promise to aid this task by learning patterns of disease progression from large corpora of health records to predict detailed outcomes for an individua...

Aims/hypothesis The gut microbiome is implicated in the disease process leading to clinical type 1 diabetes, but less is known about potential changes in the gut microbiome after the diagnosis of type 1 diabetes and implications in glucose homeostasis. We aimed to analyse potential associations between the gut microbiome composition and clinical an...

Headache disorders are the most common disorders of the nervous system. The lifetime prevalence of headache disorders show that some individuals never experience headache. The etiology of complete freedom from headache is not known. To assess genetic variants associated with complete freedom from headache, we performed a genome-wide association stu...

Aims/hypotheses Glucagon and glucagon-like peptide-1 (GLP-1) are derived from the same precursor; proglucagon, and dual agonists of their receptors are currently being explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated levels of endogenous glucagon (hyperglucagonaemia) have been link...

Context The role of glucagon-like peptide-1(GLP-1) in Type 2 diabetes (T2D) and obesity is not fully understood. Objective We investigate the association of cardiometabolic, diet and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D. Method We analysed cross-sectional data from the two Innovative Med...

Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects...

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic and proteomic study, we expand the number of genetic loci from 19 to 29, and identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to a larger...

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases...

Artificial intelligence (AI) and algorithms are heralded as significant solutions to the widening gap between the rising healthcare needs of ageing and multi-morbid populations and the scarcity of resources to provide such care. Objective This article investigates how the PMHnet algorithm – an AI prognostication tool developed in Denmark to predic...

About 1 in 9 older adults over 65 has Alzheimer's disease (AD), many of whom also have multiple other chronic conditions such as hypertension and diabetes, necessitating careful monitoring through laboratory tests. Understanding the patterns of laboratory tests in this population aids our understanding and management of these chronic conditions alo...

Background The emerging use of biomarkers in research and tailored care introduces a need for information about the association between biomarkers and basic demographics and lifestyle factors revealing expectable concentrations in healthy individuals while considering general demographic differences. Methods A selection of 47 biomarkers, including...

Objective We aimed to investigate associations between disease manifestations of SLE and HLA risk alleles relevant to Danish subjects of European ancestry. Methods HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1 alleles were assigned from whole genome sequence data of 25,215 Scandinavian samples, called by Graphtyper, and imputed into 270,627 chiptyped Dane...

Background Variation in laboratory healthcare data due to seasonal changes is a widely accepted phenomenon. Seasonal variation is generally not systematically accounted for in healthcare settings. This study applies a newly developed adjustment method for seasonal variation to analyze the effect seasonality has on machine learning model classificat...

Seasonality in laboratory healthcare data is associated with possible under- and overdiagnoses of patients in the clinic. Here, we present a protocol to analyze electronic health record data for seasonality patterns and adjust existing reference intervals for these changes using R software. We describe steps for preprocessing population-wide patien...

As a protective measure, organizations should perform regular data risk assessments to review and protect sensitive information. But what is a data risk assessment and what are good ways to perform it?

Two-thirds of all human conceptions are lost, in most cases before clinical detection. The lack of detailed understanding of the causes of pregnancy losses constrains focused counseling for future pregnancies. We have previously shown that a missense variant in synaptonemal complex central element protein 2 (SYCE2), in a key residue for the assembl...

Background Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Considerable clinical research has focused on improving graft survival and an increasing number of kidney recipients die with a functioning graft. There is a need to improve patient survival and to better understand the individualized risk of com...

Social trust is a heritable trait that has been linked with physical health and longevity. In this study, we performed genome-wide association studies of self-reported social trust in n = 33,882 Danish blood donors. We observed genome-wide and local evidence of genetic similarity with other brain-related phenotypes and estimated the single nucleoti...

Importance Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology a...

Context It is not clear if antagonizing the GIP (glucose-dependent insulinotropic polypeptide) receptor (GIPR) for treatment of obesity is likely to increase the risk of fractures, or to lower bone mineral density (BMD) beyond what is expected with rapid weight loss. Objective The objective of this study was to investigate the risk of fracture and...

Aims/hypotheses: Glucagon and Glucagon-like peptide-1 (GLP-1) are derived from the same precursor; proglucagon (gcg), and dual agonists of their receptors are currently explored for the treatment of obesity and steatotic liver disease. Elevated levels of endogenous glucagon (hyperglucagonaemia) have been linked with hyperglycaemia in individuals wi...

ELife digest Pancreatic cancer is one of the deadliest cancer types. Scientists predict it will become the second largest cause of cancer-related deaths in 2030. It has few or no symptoms at early stages and often goes undetected for an extended period. As a result, patients are often diagnosed at an advanced stage when they have few treatment opti...

Background Accurate blood type data are essential for blood bank management, but due to costs, few of 43 blood group systems are routinely determined in Danish blood banks. However, a more comprehensive dataset of blood types is useful in scenarios such as rare blood type allocation. We aimed to investigate the viability and accuracy of predicting...

Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performe...

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-ass...

Social trust is a heritable trait that has been linked with physical health and longevity. In this study, we performed genome-wide association studies of self-reported social trust in n=33,882 Danish blood donors. We observed genome-wide and local evidence of genetic similarity with other brain-related phenotypes, and estimated the single nucleotid...

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical ris...

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classi...

paragraph Heart failure (HF), a syndrome of symptomatic fluid overload due to cardiac dysfunction, is the most rapidly growing cardiovascular disorder. Despite recent advances, mortality and morbidity remain high and treatment innovation is challenged by limited understanding of aetiology in relation to disease subtypes. Here we harness the de-conf...

Dilated cardiomyopathy (DCM) is a primary heart muscle disorder that has been associated with both monogenic and polygenic architectures, with the majority of cases having no molecular genetic diagnosis. To improve our understanding of the genetic basis of DCM, we perform a genome-wide association study (GWAS) meta-analysis comprising 14,255 DCM ca...

Polypharmacy has generally been assessed by raw counts of different drugs administered concomitantly to the same patients; not with respect to the likelihood of dosage-adjustments. To address this aspect of polypharmacy, the objective of the present study was to identify co-medications associated with more frequent dosage adjustments. The data foun...

Background YKL-40, also known as chitinase-3-like protein 1 (CHI3L1), is a secreted glycoprotein produced by various cell types including stromal, immune, and cancer cells. It contributes to cancer progression through tumor-promoting inflammation and has been shown to inhibit the cytotoxicity of T and NK lymphocytes. In vivo studies have demonstrat...

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic r...

Objective Combining population‐based health registries and electronic health records offers the opportunity to create large, phenotypically detailed patient cohorts of high quality. In this study, we used text mining of clinical notes to confirm International Classification of Diseases, 10th Revision (ICD‐10)‐registered epilepsy diagnoses and class...

Novel biomarkers are key to addressing the ongoing pandemic of type 2 diabetes mellitus. While new technologies have improved the potential of identifying such biomarkers, at the same time there is an increasing need for informed prioritization to ensure efficient downstream verification. We have built BALDR, an automated pipeline for biomarker com...

Background Pregnancy is a complex biological process and serious complications can arise when the delicate balance between the maternal immune system and the semi-allogeneic fetal immune system is disrupted or challenged. Gestational diabetes mellitus (GDM), pre-eclampsia, preterm birth, and low birth weight, pose serious threats to maternal and fe...

Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severity of these complications in maternal-fetal health. Here, we investigated the genetic variation underlying aspects of pregnancy-a...