Bjarni Jóhann Vilhjálmsson

• PhD
• Professor at Aarhus University

Background Previous research has shown that females who use hormonal contraception are at increased risk of developing depression, and that the risk is highest among adolescents. While this finding could reflect age‐specific effects of exogenous hormones on mental health, genetic liability for mental disorders could be confounding the association....

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic ass...

Background The clinical course of major depressive disorder (MDD) is heterogeneous, and early-onset MDD often has a more severe and complex clinical course. Our goal was to determine whether polygenic scores (PGSs) for psychiatric disorders are associated with treatment trajectories in early-onset MDD treated in secondary care. Methods Data were d...

Genome–wide association studies (GWAS) have discovered thousands of replicable genetic associations, guiding drug target discovery and powering genetic prediction of human phenotypes and diseases. However, genetic associations can be affected by gene–environment correlations and non–random mating, which can lead to biased inferences in downstream a...

Objective Eating disorders (EDs) are serious psychiatric disorders with an estimated 3.3 million healthy life-years lost worldwide yearly. Understanding the course of illness, diagnostic transitions and remission, and their associated genetic correlates could inform both ED etiology and treatment. The authors investigated occurrences of ED transiti...

Purpose: Childhood incontinence is stigmatized and underprioritized, and a basic understanding of its pathogenesis is missing. Our goal was to identify risk-conferring genetic variants in daytime urinary incontinence (DUI). Materials and methods: We conducted a genome-wide association study in the Danish iPSYCH2015 cohort. Cases (3024) were iden...

Although thousands of genetic variants are linked to human traits and diseases, the underlying mechanisms influencing these traits remain largely unexplored. One important aspect is to understand how proteins are regulated by the genome by identifying protein quantitative trait loci (pQTLs). Beyond this, there is a need to understand the role of co...

Background Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM. Methods We...

While it is known that vitamin D deficiency is associated with adverse bone outcomes, it remains unclear whether low vitamin D status may increase the risk of a wider range of health outcomes. We had the opportunity to explore the association between common genetic variants associated with both 25 hydroxyvitamin D (25OHD) and the vitamin D binding...

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic ass...

Background Although several types of risk factors for anorexia nervosa (AN) have been identified, including birth-related factors, somatic, and psychosocial risk factors, their interplay with genetic susceptibility remains unclear. Genetic and epidemiological interplay in AN risk were examined using data from Danish nationwide registers. AN polygen...

Despite great progress on methods for case-control polygenic prediction (e.g. schizophrenia vs. control), there remains an unmet need for a method that genetically distinguishes clinically related disorders (e.g. schizophrenia (SCZ) vs. bipolar disorder (BIP) vs. depression (MDD) vs. control); such a method could have important clinical value, espe...

Complement components have been linked to schizophrenia and autoimmune disorders. We examined the association between neonatal circulating C3 and C4 protein concentrations in 68,768 neonates and the risk of six mental disorders. We completed genome-wide association studies (GWASs) for C3 and C4 and applied the summary statistics in Mendelian random...

It remains inconclusive whether postpartum depression (PPD) and depression with onset outside the postpartum period (MDD) are genetically distinct disorders. We aimed to investigate whether polygenic risk scores (PGSs) for major mental disorders differ between PPD cases and MDD cases in a nested case-control study of 50,057 women born from 1981 to...

Low birth weight has been associated with a higher risk of psychiatric disorders later in life. The underlying causal mechanisms of this relationship are however not clear. In this study, we investigate whether variation in fetal growth has a direct causal effect on mental health. Using birth weight as a proxy measure for fetal growth, we first ass...

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...

Proportional hazards models have been proposed to analyse time-to-event phenotypes in genome-wide association studies (GWAS). However, little is known about the ability of proportional hazards models to identify genetic associations under different generative models and when ascertainment is present. Here we propose the age-dependent liability thre...

The predictive performance of polygenic scores (PGS) is largely dependent on the number of samples available to train the PGS. Increasing the sample size for a specific phenotype is expensive and takes time, but this sample size can be effectively increased by using genetically correlated phenotypes. We propose a framework to generate multi-PGS fro...

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which a...

The state-of-the-field in complex disorder genetics is marked by large-scale, biobank-ascertained data sets that integrate broad demographic, health, survey, and genetic data. Leveraging the richness of this data can advance our understanding of complex disorders by improving predictions, describing etiology, and augmenting gene-mapping. These them...

Polygenic risk scores (PRS) trained from genome-wide association study (GWAS) results are set to play a pivotal role in biomedical research addressing multifactorial human diseases. The prospect of using these risk scores in clinical care and public health is generating both enthusiasm and controversy, with varying opinions about strengths and limi...

Genetics as a science has roots in studying phenotypes of relatives, but molecular approaches facilitate direct measurements of genomic variation within individuals. Agricultural and human biomedical research are both emphasizing genotype-based instruments, like polygenic scores, as the future of breeding programs or precision medicine and genetic...

Risk prediction can inform clinical decision-making from screening protocols all the way through to treatment and informed lifestyle changes. Increasingly, genetic tests are becoming available, making disease risk prediction at a personalized level even more possible. Depending on the genetic architecture of a given phenotype, different approaches...

Objective To examine sex differences in risk factors for anorexia nervosa (AN). Method This population‐based study involved 44,743 individuals (6,239 AN cases including 5,818 females and 421 males, and 38,504 controls including 18,818 females and 19,686 males) born in Denmark between May 1981 and December 2009. Follow‐up began on the individual's...

Polygenic risk scores (PRSs) are expected to play a critical role in precision medicine. Currently, PRS predictors are generally based on linear models using summary statistics, and more recently individual-level data. However, these predictors mainly capture additive relationships and are limited in data modalities they can use. We developed a dee...

Polygenic scores (PGSs) have limited portability across different groupings of individuals (for example, by genetic ancestries and/or social determinants of health), preventing their equitable use1–3. PGS portability has typically been assessed using a single aggregate population-level statistic (for example, R²)⁴, ignoring inter-individual variati...

The vitamin D binding protein (DBP), encoded by the group-specific component (GC) gene, is a component of the vitamin D system. In a genome-wide association study of DBP concentration in 65,589 neonates we identify 26 independent loci, 17 of which are in or close to the GC gene, with fine-mapping identifying 2 missense variants on chromosomes 12 an...

Objective: The authors investigated associations between polygenic liabilities for bipolar disorder, major depression, and schizophrenia and episode polarity among individuals with bipolar disorder. Methods: The sample consisted of 2,705 individuals diagnosed with bipolar disorder at Danish psychiatric hospitals between January 1995 and March 20...

Objective We developed an assay to measure the concentration of 25 hydroxyvitamin D 2 and D 3 in protein extracts derived from stored neonatal dried blood spots. During this study, we postulated that these samples had been contaminated with exogenous vitamin D metabolites because of the addition of bovine serum albumin (BSA) as part of an extractio...

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight after term delivery 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-s...

The complement system, including complement components 3 and 4 (C3, C4), traditionally has been linked to innate immunity. More recently, complement components have also been implicated in brain development and the risk of schizophrenia. Based on a large, population-based case-cohort study, we measured the blood concentrations of C3 and C4 in 68,76...

Blood and urine biomarkers are an essential part of modern medicine, not only for diagnosis, but also for their direct influence on disease. Many biomarkers have a genetic component, and they have been studied extensively with genome-wide association studies (GWAS) and methods that compute polygenic scores (PGSs). However, these methods generally a...

LDpred2 is a widely used Bayesian method for building polygenic scores (PGS). LDpred2-auto can infer the two parameters from the LDpred model, h ² and p , so that it does not require an additional validation dataset to choose best-performing parameters. Here, we present a new version of LDpred2-auto, which adds a third parameter α to its model for...

Recently, several new approaches for creating polygenic scores (PGS) have been developed and this trend shows no sign of abating. However, it has thus far been challenging to determine which approaches are superior, as different studies report seemingly conflicting benchmark results. This heterogeneity in benchmark results is in part due to differe...

Polygenic scores (PGS) have limited portability across different groupings of individuals (e.g., by genetic ancestries and/or social determinants of health), preventing their equitable use. PGS portability has typically been assessed using a single aggregate population-level statistic (e.g., R2), ignoring inter-individual variation within the popul...

The predictive performance of polygenic scores (PGS) in clinical risk models is largely dependent on the number of samples available to train the score, together with the proportion of causal variants and heritability of the phenotype and and discovery-target cohort heterogeneity. Increasing the number of samples for a specific phenotype can be exp...

Objective: Attention deficit hyperactivity disorder (ADHD) is a multifactorial neurodevelopmental disorder, yet the interplay between ADHD polygenic risk scores (PRSs) and other risk factors remains relatively unexplored. The authors investigated associations, confounding, and interactions of ADHD PRS with birth-related, somatic, and psychosocial...

Major depression (MD) is a common mental disorder and a leading cause of disability worldwide. We conducted a GWAS meta-analysis of more than 1.3 million individuals, including 371,184 with MD, identifying 243 risk loci. Sixty-four loci are novel, including glutamate and GABA receptors that are targets for antidepressant drugs. Several biological p...

Proportional hazards models have previously been proposed to analyse time-to-event phenotypes in genome-wide association studies(GWAS). While proportional hazards models have many useful applications, their ability to identify genetic associations under different generative models where ascertainment is present in the analysed data is poorly unders...

Publicly available genome-wide association studies (GWAS) summary statistics exhibit uneven quality, which can impact the validity of follow-up analyses. First, we present an overview of possible misspecifications that come with GWAS summary statistics. Then, in both simulations and real data analyses, we show that additional information such as im...

Objective: To evaluate the influence of extensive genetic and psychosocial confounding on the association between early childhood infection and five major psychiatric disorders. Methods: A case-cohort study including participants from the Danish iPSYCH2012 sample, a case-cohort sample where all cases born between May 1, 1981, and December 31, 20...

Background Childbirth may be a traumatic experience and vulnerability to posttraumatic stress disorder (PTSD) may increase the risk of postpartum depression (PPD). We investigated whether genetic vulnerability to PTSD as measured by polygenic score (PGS) increases the risk of PPD and whether a predisposition to PTSD in PPD cases exceeds that of maj...

The vitamin D binding protein (DBP), encoded by the group-specific component (GC) gene, is a much-studied component of the vitamin D system. In a genome-wide association study of DBP concentration in 65,589 neonates, we identified 26 independent loci, 17 of which were in or close to the GC gene, with fine-mapping identifying 2 loci on chromosomes 1...

(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.;...

Genome-wide association studies (GWASs) have revolutionized human genetics, allowing researchers to identify thousands of disease-related genes and possible drug targets. However, case-control status does not account for the fact that not all controls may have lived through their period of risk for the disorder of interest. This can be quantified b...

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls id...

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...

Objective: To estimate phenotypic and familial association between early-life injuries and attention-deficit/hyperactivity disorder (ADHD) and the genetic contribution to the association using polygenic risk score for ADHD (PRS-ADHD) and genetic correlation analyses. Methods: Children born in Denmark between 1995-2010 (n = 786,543) were followed f...

Although the cohort-level accuracy of polygenic risk scores (PRSs)—estimates of genetic value at the individual level—has been widely assessed, uncertainty in PRSs remains underexplored. In the present study, we show that Bayesian PRS methods can estimate the variance of an individual’s PRS and can yield well-calibrated credible intervals via poste...

Psychiatric family history or a high autism polygenic risk score (PRS) have been separately linked to autism spectrum disorder (ASD) risk. The study aimed to simultaneously consider psychiatric family history and individual autism genetic liability (PRS) in autism risk. We performed a case–control study of all Denmark singleton births, May 1981–Dec...

Background: Anorexia nervosa (AN), a serious eating disorder, and inflammatory bowel diseases (IBD) share a number of key symptoms, for example, discomfort during eating and early satiety. Despite the symptom overlap, studies on comorbidity are limited and mostly conducted in relatively small samples. This study investigates the comorbidity of dia...

Genome-wide association studies (GWASs) have uncovered a wealth of associations between common variants and human phenotypes. Here, we present an integrative analysis of GWAS summary statistics from 36 phenotypes to decipher multitrait genetic architecture and its link with biological mechanisms. Our framework incorporates multitrait association ma...

Background: ADHD is multifactorial, yet the interplay ADHD polygenic risks scores (ADHD-PRS) and other ADHD associated risk-factors remains relatively unexplored. The aim of this study was to investigate associations, confounding and interactions of ADHD-PRS with birth, somatic and psychosocial risk-factors previously associated with ADHD. Methods:...

Most existing tools for constructing genetic prediction models begin with the assumption that all genetic variants contribute equally towards the phenotype. However, this represents a suboptimal model for how heritability is distributed across the genome. Therefore, we develop prediction tools that allow the user to specify the heritability model....

Over the last half century, a body of convergent evidence has accumulated linking disruption of early brain development with an increased risk of mental disorders, including schizophrenia. The orderly cascade of brain development may be disrupted by exposure to suboptimal concentrations of a range of biological substrates and micronutrients. We hyp...

Objective: Stimulant medications are effective for treating attention deficit hyperactivity disorder (ADHD), yet discontinuation and switch to nonstimulant ADHD medications are common. This study aimed to identify genetic, clinical, and sociodemographic factors influencing stimulant treatment initiation, discontinuation, and switch to nonstimulant...

Polygenic risk scores (PRSs) are expected to play a critical role in achieving precision medicine. PRS predictors are generally based on linear models using summary statistics, and more recently individual- level data. However, these predictors generally only capture additive relationships and are limited when it comes to what type of data they use...

Background - Polygenic risk scores (PRSs) are associated with coronary artery disease (CAD), but the clinical potential of using PRSs at the single-patient level for risk stratification has yet to be established. We investigated whether adding a PRS to clinical risk factors (CRFs) improves risk stratification in patients referred to coronary comput...

Risk of major depression (MD) is determined partly by genetic factors, and evidence from family studies suggests that individuals who experience recurrent MD might have a higher genetic loading.¹ Studies have demonstrated that MD is polygenic, meaning multiple genetic variants contribute to risk of MD.² Wray et al² found an association between poly...

Background: In this study, we examined the relationship between polygenic liability for depression and number of stressful life events (SLEs) as risk factors for early-onset depression treated in inpatient, outpatient or emergency room settings at psychiatric hospitals in Denmark. Methods: Data were drawn from the iPSYCH2012 case-cohort sample,...

The accuracy of polygenic risk scores (PRSs) to predict complex diseases increases with the training sample size. PRSs are generally derived based on summary statistics from large meta-analyses of multiple genome-wide association studies (GWASs). However, it is now common for researchers to have access to large individual-level data as well, such a...

Genome-wide association studies (GWAS) have revolutionized human genetics, allowing researchers to identify thousands of disease-related genes and possible drug targets. However, case-control status does not account for the fact that not all controls may have lived through their period of risk for the disorder of interest. This can be quantified by...