Harold Snieder

University of Groningen | RUG · Department of Epidemiology

Background: Multimorbidity is linked to poor quality of life, and increased healthcare costs, and multimorbidity risk is potentially mitigated by a healthy lifestyle. This study evaluated the individual and joint contributions of an extensive set of lifestyle factors to the development of multimorbidity. Methods: A prospective study of 133,719 adul...

Autism spectrum disorder (ASD) often co-occurs with functional somatic syndromes (FSS), such as irritable bowel syndrome (IBS), multisite pain, and fatigue. However, the underlying genetic mechanisms and causality have not been well studied. Using large-scale genome-wide association study (GWAS) data, we investigated the shared genetic architecture...

Emerging evidence suggests that ADHD is associated with increased risk for metabolic and cardiovascular (cardiometabolic) diseases. However, an understanding of the mechanisms underlying these associations is still limited. In this study we estimated the associations of polygenic scores (PGS) for ADHD with several cardiometabolic diseases and bioma...

Altered affect and cognitive dysfunction are transdiagnostic, burdensome, and pervasive features of many psychiatric conditions which remain poorly understood and have few efficacious treatments. Research on the genetic architecture of these phenotypes and causal relationships between them may provide insight into their aetiology and comorbidity. U...

Aims Type 2 diabetes (T2D) is a global health burden, more prevalent among individuals with attention deficit hyperactivity disorder (ADHD) compared to the general population. To extend the knowledge base on how ADHD links to T2D, this study aimed to estimate causal effects of ADHD on T2D and to explore mediating pathways. Methods We applied a two...

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...

Background Hair dyes are widely used in daily life. However, data on self‐reported adverse skin reactions are scarce. Objectives To estimate the proportion of lifetime hair dye use and self‐reported adverse skin reactions in the Dutch general population, and to investigate the association between (adverse skin reactions to) hair dye use and contac...

We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify novel genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. We collected data from 55 cohorts with a combined sample size of 732,564 participants (87% European ancestry)...

Background Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome‐wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular r...

A healthy diet prevents overweight problems and hypertension. We investigated the associations of a healthy diet with the body mass index (BMI) and blood pressure (BP) in early childhood. In the GECKO birth cohort, height, weight, and BP were measured at 5 and 10 years of age. Diet was evaluated at 3 years using three diet scores: the Dietary Appro...

Objectives: Interleukin 6 (IL-6) levels at hospital admission have been suggested for disease prognosis, and IL-6 antagonists have been suggested for the treatment of patients with severe COVID-19. However, less is known about the relationship between pre-COVID-19 IL-6 levels and the risk of severe COVID-19. To fill in this gap, here we extensively...

Background Twin studies revealed that genetic effects play a role in hand eczema (HE), but the responsible genetic factors are unknown. Objectives To identify and characterise genetic loci associated with HE and to provide insight into the genetic overlap between HE and atopic dermatitis (AD). Methods We used questionnaire‐derived and genotype da...

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE....

Autistic children often have comorbid somatic problems. However, in adulthood, this has been much less studied. We investigated the associations between autistic symptoms and irritable bowel syndrome, food allergy, pain, and fatigue in adulthood and examined sex and life-course differences herein. A total of 35,048 adults aged from 18 to 90 from th...

Inflammation is associated with a range of neuropsychiatric symptoms; however, the nature of the causal relationship is unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognition. W...

We develop a method, SBayesRC, that integrates genome-wide association study (GWAS) summary statistics with functional genomic annotations to improve polygenic prediction of complex traits. Our method is scalable to whole-genome variant analysis and refines signals from functional annotations by allowing them to affect both causal variant probabili...

Background: Low-grade systemic inflammation is implicated in the pathogenesis of various neuropsychiatric conditions affecting mood and cognition. While much of the evidence concerns depression, large-scale population studies of anxiety, affect, and cognitive function are scarce. Importantly, causality remains unclear. We used complementary non-gen...

Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder for which genetic factors explain up to 75% of the variance. In this study, we performed a genome-wide association meta-analysis (GWAMA) of ADHD symptom measures, with an effective sample size of 120,092 (71,733 unique individuals from 28 population-based coh...

Altered blood pressure (BP) circadian rhythmicity has been increasingly linked with cardiovascular risk. However, little is known about BP circadian rhythm change with age and its possible sociodemographic, anthropometric, and genetic moderators. Twenty-four-hour ambulatory BP was measured up to 16 times over a 23-year period in 339 European Americ...

Vesicular hand eczema (VHE), a clinical subtype of hand eczema (HE), showed limited responsiveness to alitretinoin, the only approved systemic treatment for severe chronic HE. This emphasizes the need for alternative treatment approaches. Therefore, our study aimed to identify drug repurposing opportunities for VHE using transcriptomics and genomic...

Introduction Blood pressure (BP) is a highly heritable trait with over 2000 underlying genomic loci identified to date. Although the kidney plays a key role, little is known about specific cell types involved in the genetic regulation of BP. Methods Here, we applied stratified linkage disequilibrium score (LDSC) regression to connect BP genome-wid...

DNA methylation (DNAm) is a developmentally dynamic epigenetic process, yet we still know little about how epigenetic effects on health outcomes vary over time; whether DNAm alterations during certain periods of development are more informative than others; and whether epigenetic timing effects differ by outcome. To address these questions, we appl...

Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dat...

Purpose: Glaucoma screening potentially prevents blindness but is currently considered not cost effective due to insufficient screening test specificity given a low disease prevalence in the general population. Genetic pre‐screening could increase the prior probability (higher prevalence in a selected population). The aim of this study was to ident...

We conducted a genome-wide association study (GWAS) on income among individuals of European descent and leveraged the results to investigate the socio-economic health gradient (N=668,288). We found 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes. Our GWAS-derived polygenic ind...

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE....

We conducted a genome-wide association study (GWAS) on income among individuals of European descent and leveraged the results to investigate the socio-economic health gradient ( N =668,288). We found 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes. Our GWAS-derived polygenic i...

Platelet count has been associated with blood pressure, but whether this association reflects causality remains unclear. To strengthen the evidence, we conducted a traditional observational analysis in the Lifelines Cohort Study (n = 167,785), and performed bi-directional Mendelian randomization (MR) with summary GWAS data from the UK Biobank (n =...

Introduction: Acute kidney injury (AKI) is a global concern with high incidence and poor prognosis among critically ill patients. As AKI is frequently only detected well after its onset, early risk stratification is crucial. We aimed to develop and internally validate the first clinical prediction model for different stages of AKI occurring within...

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from h...

Background Although often intended for long-term treatment, discontinuation of medication for ADHD is common. However, cross-national estimates of discontinuation are missing due to the absence of standardised measures. The aim of this study was to determine the rate of ADHD treatment discontinuation across the lifespan and to describe similarities...

Background It is unclear to what extent genetics explain the familial clustering and the co-occurrence of distinct cardiometabolic disorders in the general population. We therefore aimed to quantify the familial (co-)aggregation of various cardiometabolic disorders and to estimate the heritability of cardiometabolic traits and their genetic correla...

Low heart rate variability (HRV) has been widely reported as a predictor for increased mortality. However, the molecular mechanisms are poorly understood. Therefore, this study aimed to identify novel genetic loci associated with HRV and assess the association of phenotypic HRV and genetically predicted HRV with mortality. In a GWAS of 46,075 Europ...

Autism spectrum disorder (ASD) often co-occurs with functional somatic syndromes (FSS), such as irritable bowel syndrome (IBS), pain, and fatigue. However, the underlying genetic mechanisms and causality have not been well studied. Using large-scale genome-wide association study (GWAS) data, we investigated the shared genetic architecture and causa...

Background Multimorbidity is associated with poor quality of life, polypharmacy, health care costs and mortality, with those affected potentially benefitting from a healthy lifestyle. We assessed a comprehensive set of lifestyle factors in relation to multimorbidity with major chronic diseases. Methods This cross-sectional study utilised baseline...

Background: Previous studies have found associations of red blood cell traits (hemoglobin and red blood cell count, RBC) with blood pressure; whether these associations are causal is unknown. Methods: We performed cross-sectional analyses in the Lifelines Cohort Study (n=167,785). Additionally, we performed bidirectional two sample Mendelian ran...

Objective: This study investigated cross-sectional and longitudinal associations of fast-food outlet exposure with BMI and BMI change, as well as moderation by age and genetic predisposition. Methods: This study used Lifelines' baseline (n = 141,973) and 4-year follow-up (n = 103,050) data. Participant residential addresses were linked to a regi...

Background It is unclear how cardiac autonomic function, as indicated by heart rate (HR), heart rate variability (HRV), HR increase during exercise, and HR recovery after exercise, is related to blood pressure (BP). We aimed to examine the observational and genetic evidence for a potential causal effect of these HR(V) traits on BP. Methods We perf...

The present study investigated whether an unhealthy diet and other lifestyle behaviors may modify the genetic susceptibility to impulsivity. A total of 33,047 participants (mean age = 42.1 years, 59.8% females) from the Dutch Lifelines cohort were included. Each diet index and other lifestyle behaviors were tested for their interactions on the effe...

It is unclear whether and to what extent stress-related exposures moderate the effects of polygenic risk scores (PRSs) on depression and anxiety. We aimed to examine such moderation effects for a variety of stress-related exposures on depression and anxiety. We included 41,810 participants with both genome-wide genetic data and measurements of depr...

The genetic regulation of post-prandial glucose levels is poorly understood. Here, we characterise the genetic architecture of blood glucose variably measured within 0 and 24 h of fasting in 368,000 European ancestry participants of the UK Biobank. We found a near-linear increase in the heritability of non-fasting glucose levels over time, which pl...

The c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, there are carriers who remain asymptomatic at older ages. To understand the mechanisms behind this incomplete penetrance, we evaluated potenti...

Objective: Midlife in women is associated with an increase in prevalence of hypertension. Little is known on the risk factors of new-onset hypertension among middle-aged women. Methods: In this nested case-control study, 1,430 women aged 40 to 60 years with repeated physical examinations between 2009 and 2019 were recruited. Data included age, b...

We develop a new method, SBayesRC, that integrates GWAS summary statistics with functional genomic annotations to improve polygenic prediction of complex traits. Our method is scalable to whole-genome variant analysis and refines signals from functional annotations by allowing them to affect both causal variant probability and causal effect distrib...

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypi...

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8,058) with genotyp...

BACKGROUND In mice, GPR146 (G-protein–coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown. METHODS Common and rare genetic variants in the GPR146 gene locus were used as research instruments in the UK-Biobank. The Lifelines, and The Copenhagen-City Heart...

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. W...

As the histology, physiology, and pathophysiology of eyes and kidneys show substantial overlap, it has been suggested that eye and kidney diseases, such as glaucoma and chronic kidney disease (CKD), may be closely interlinked. We review the relationship between CKD and various subtypes of glaucoma, including primary open-angle glaucoma, primary ang...

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in...

DNA methylation (DNAm) patterns across the genome changes during aging and development of complex diseases including type 2 diabetes (T2D). Our study aimed to estimate DNAm trajectories of CpG sites associated with T2D, epigenetic age (DNAmAge), and age acceleration based on four epigenetic clocks (GrimAge, Hannum, Horvath, phenoAge) in the period...

Aims/hypothesis Type 2 diabetes mellitus is a major health burden disproportionately affecting those with lower educational attainment (EA). We aimed to obtain causal estimates of the association between EA and type 2 diabetes and to quantify mediating effects of known modifiable risk factors. Methods We applied two-step, two-sample multivariable...

One important confounder in genome-wide association studies (GWASs) is population genetic structure, which may generate spurious associations if not properly accounted for. This may ultimately result in a biased polygenic risk score (PRS) prediction, especially when applied to another population. To explore this matter, we focused on principal comp...

Objective: Previous studies have shown negative associations between total bilirubin (TBIL) and hypertension. However, the association of TBIL with new-onset hypertension in perimenopausal women is unknown. Methods: A total of 196 perimenopausal women were included in this cross-sectional study of which 85 had new-onset hypertension. All partici...

Recent genome-wide association studies uncovered part of blood pressure’s heritability. However, there is still a vast gap between genetics and biology that needs to be bridged. Here, we followed up blood pressure genome-wide summary statistics of over 750,000 individuals, leveraging comprehensive epigenomic and transcriptomic data from blood with...

Introduction Isfahan functional disorders (ISFUN) cohort study aims to describe the interplay of genetic and environmental factors in shaping the characteristics of functional somatic syndromes (FSS). This study is primarily intended to investigate the epidemiology, risk factors, course and prognosis of FSSs in a sample of adult Iranian population....

Background: Primary open-angle glaucoma (POAG) is the most prevalent glaucoma subtype, but its exact etiology is still unknown. In this study, we aimed to prioritize the most likely 'causal' genes and identify functional characteristics and underlying biological pathways of POAG candidate genes. Methods: We used the results of a large POAG genom...

Physical and mental health are determined by an interplay between nature, for example genetics, and nurture, which encompasses experiences and exposures that can be short or long-lasting. The COVID-19 pandemic represents a unique situation in which whole communities were suddenly and simultaneously exposed to both the virus and the societal changes...

The c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, other carriers remain asymptomatic or show only mild symptoms in old age. To understand the mechanisms behind this incomplete penetrance, we e...

BACKGROUND AND AIMS The genetics of kidney function has been extensively studied, but since these analyses have been done mostly in populations with normal or mildly impaired kidney function, it is still unknown whether variants linked to kidney function also translate into genetic susceptibility for kidney failure. The primary aim of this study wa...

Aims/hypothesis Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by com...