Jan H. Veldink's research while affiliated with Utrecht University and other places

Publications (550)

Article
Full-text available
Background The Gold Coast criteria (GCC) have been proposed as a means of selecting patients for amyotrophic lateral sclerosis (ALS) clinical trials. We aimed to characterise disease progression according to the GCC. Methods Data from population-based ALS registries from the Netherlands and Belgium were analysed. The GCC additionally define ALS as...
Preprint
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Selective vulnerability of energy-intensive motor neurons (MNs) has fostered speculation that mitochondrial function is a determinant of ALS. Previously, the position of mitochondrial function in the pathogenic cascade leading to neurotoxicity has been unclear. We separated u...
Preprint
Background Rupture of an intracranial aneurysm (IA) causes aneurysmal subarachnoid hemorrhage (ASAH). There is no accurate prediction model for IA or ASAH in the general population. Recent discoveries in genetic risk for IA may allow improved risk prediction. Methods We constructed a genetic risk score including genetic association data for IA and...
Preprint
Background Humans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how commo...
Article
Full-text available
Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic...
Article
Full-text available
Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association...
Article
Full-text available
The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS c...
Article
Full-text available
Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and ident...
Article
Full-text available
Rupture of an intracranial aneurysm (IA) leads to aneurysmal subarachnoid haemorrhage (ASAH), a severe type of stroke. Some rare variants that cause IA in families have been identified, but still, the majority of genetic causes, as well as the biological mechanisms of IA development and rupture, remain unknown. We aimed to identify rare, damaging v...
Preprint
Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects 1 in 400 people. Almost 40 genes have been associated with ALS, currently explaining about 15% of the ALS risk. These genes tend to cluster in certain disease pathways such as protein quality control, RNA metabolism and axonal function. Despite t...
Article
Full-text available
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide a...
Article
Full-text available
The objective of this study was to examine if patterns of resting-state brain activity and functional connectivity in cortical and subcortical regions in patients with early symptomatic amyotrophic lateral sclerosis (ALS) resemble those of behavioural variant frontotemporal dementia (bvFTD). In a cross-sectional design, eyes-closed resting-state ma...
Article
Full-text available
There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwi...
Article
Full-text available
Background Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausibl...
Article
Full-text available
Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. W...
Article
Full-text available
Background Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore whether the deviation of predicted age from chronological age is associated with disease phenotypes, where this deviation is interpreted as a pot...
Article
Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that...
Article
Full-text available
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 indi...
Article
Full-text available
Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of...
Article
Full-text available
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 indi...
Preprint
Full-text available
Objective: To determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS). Methods: We performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across No...
Article
Full-text available
Objectives To investigate sensitivity of brain MRI and neurological examination for detection of upper motor neuron (UMN) degeneration in patients with amyotrophic lateral sclerosis (ALS). Methods We studied 192 patients with ALS and 314 controls longitudinally. All patients visited our centre twice and underwent full neurological examination and...
Article
Full-text available
Evidence indicates that common variants found in genome-wide association studies increase risk of disease through gene regulation via expression Quantitative Trait Loci. Using multiple genome-wide methods we examined if Single Nucleotide Polymorphisms increase risk of Amyotrophic Lateral Sclerosis through expression Quantitative Trait Loci, and whe...
Article
Full-text available
Importance Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants In this multicenter family-based genetic study, trio whole-exome sequencing was...
Article
Full-text available
Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-e...
Article
Full-text available
Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We...
Article
Full-text available
Importance Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants In this multicenter family-based genetic study, trio whole-exome sequencing w...
Preprint
Full-text available
The genetic basis of amyotrophic lateral sclerosis (ALS) is still incompletely understood. Using two independent genetic strategies, we show here that a large part of ALS heritability lies in genes expressed in inhibitory and excitatory neurons, especially at splicing sites regulated by a defined set of RNA binding proteins including TDP-43 and FUS...
Article
Full-text available
Purpose of review: Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease wherein disease risk and severity are, for the majority of patients, the product of interaction between multiple genetic and environmental factors. We are in a period of unprecedented discovery with new large-scale genome-wide association study (GWAS) and accel...
Preprint
Full-text available
The non-coding genome is substantially larger than the protein-coding genome, but the lack of appropriate methodologies for identifying functional variants limits genetic association studies. Here, we developed analytical tools to identify rare variants in pre-miRNAs, miRNA recognition elements in 3’UTRs, and miRNA-target networks. Region-based bur...
Article
Background Amyotrophic lateral sclerosis (ALS) is considered to be caused by both genetic and environmental factors. The causal cascade is, however, not known. We aimed to assess lifestyle during the presymptomatic phase of ALS, stratified by C9orf72 mutation, and examine evidence supporting causality of lifestyle factors. Methods This study was a...
Article
Full-text available
The kinesin family member 5A (KIF5A) motor domain variants are typically associated with hereditary spastic paraplegia (HSP) or Charcot-Marie-Tooth 2 (CMT2), while KIF5A tail variants predispose to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus. Variants within the stalk domain of KIF5A are relatively rare. We describe a fam...
Article
Full-text available
Apart from well-defined factors in neuronal cells¹, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels⁴. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord sampl...
Article
Full-text available
Background People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and th...
Preprint
Full-text available
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability of around 50%. DNA methylation patterns can serve as biomarkers of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide ass...
Preprint
Full-text available
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced indivi...
Preprint
Full-text available
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced indivi...
Preprint
Gaining insight into the downstream consequences of non-coding variants is an essential step towards the identification of therapeutic targets from genome-wide association study (GWAS) findings. Here we have harmonized and integrated 8,727 RNA-seq samples with accompanying genotype data from multiple brain-regions from 14 datasets. This sample size...
Article
Full-text available
The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank particip...
Article
Full-text available
(Cell Reports 33, 108456-1–108456-8.e1–e5; December 1, 2020) In the originally published version of this article, Eran Elhaik was incorrectly spelled in the author list. The corrected author list appears here and with the article online. The authors regret the error.
Article
Full-text available
Objective To assess time trends in MND incidence, prevalence and mortality and investigate geographical clustering of MND cases in the Netherlands from 1998 to 2017, we analyzed data from the Netherlands Personal Records database, the Netherlands MND Center and the Netherlands Patient Association of Neuromuscular Diseases. Methods In this prospect...
Article
Full-text available
Genetic isolates are compelling tools for mapping genes of inherited disorders. The archipelago of Malta, a sovereign microstate in the south of Europe is home to a geographically and culturally isolated population. Here, we investigate the epidemiology and genetic profile of Maltese patients with amyotrophic lateral sclerosis (ALS), identified thr...
Article
Full-text available
Objective The role of Survival of Motor Neuron gene (SMN) in Amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. Methods In this largest multicentre case control study to evaluate the effect of SMN1 and SMN2 c...
Article
Full-text available
Illumina DNA methylation arrays are a widely used tool for performing genome-wide DNA methylation analyses. However, measurements obtained from these arrays may be affected by technical artefacts that result in spurious associations if left unchecked. Cross-reactivity represents one of the major challenges, meaning that probes may map to multiple r...
Preprint
Full-text available
Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease centered on progressive death of motor neurons. Despite heritability estimates of 52%, GWAS studies have discovered only seven genome-wide significant hits, which are relevant to <10% of ALS patients. To increase the power of gene discovery, we integrated motor neuron functional g...
Article
Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of whic...
Article
Full-text available
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding ge...
Article
Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of whic...
Article
Full-text available
Objective Metals have been suggested as a risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls, to explore whether metals are associated with ALS mortality. Methods A nested ALS case–control study w...
Article
Full-text available
Previous genetic studies have identified local population structure within the Netherlands; however their resolution is limited by use of unlinked markers and absence of external reference data. Here we apply advanced haplotype sharing methods (ChromoPainter/fineSTRUCTURE) to study fine-grained population genetic structure and demographic change ac...
Preprint
Full-text available
Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We presen...
Article
Full-text available
Background: DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data. Results: By employing genetic instruments as causal anchors,...
Article
Full-text available
Objective The rs12608932 single nucleotide polymorphism in UNC13A is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype of UNC13A in ALS patients. Methods We...