ORCID Profile
0000-0001-9938-7126
Current Organisation
University of Luxembourg
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Publisher: Oxford University Press (OUP)
Date: 17-03-2015
DOI: 10.1093/BRAIN/AWV052
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 17-03-2020
DOI: 10.1186/S13073-020-00725-6
Abstract: Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 25-09-2019
DOI: 10.1002/EPI4.12360
Publisher: Life Science Alliance, LLC
Date: 24-09-2020
Abstract: Single-cell RNA-sequencing (scRNAseq) technologies are rapidly evolving. Although very informative, in standard scRNAseq experiments, the spatial organization of the cells in the tissue of origin is lost. Conversely, spatial RNA-seq technologies designed to maintain cell localization have limited throughput and gene coverage. Mapping scRNAseq to genes with spatial information increases coverage while providing spatial location. However, methods to perform such mapping have not yet been benchmarked. To fill this gap, we organized the DREAM Single-Cell Transcriptomics challenge focused on the spatial reconstruction of cells from the Drosophila embryo from scRNAseq data, leveraging as silver standard, genes with in situ hybridization data from the Berkeley Drosophila Transcription Network Project reference atlas. The 34 participating teams used erse algorithms for gene selection and location prediction, while being able to correctly localize clusters of cells. Selection of predictor genes was essential for this task. Predictor genes showed a relatively high expression entropy, high spatial clustering and included prominent developmental genes such as gap and pair-rule genes and tissue markers. Application of the top 10 methods to a zebra fish embryo dataset yielded similar performance and statistical properties of the selected genes than in the Drosophila data. This suggests that methods developed in this challenge are able to extract generalizable properties of genes that are useful to accurately reconstruct the spatial arrangement of cells in tissues.
Publisher: Wiley
Date: 04-2022
DOI: 10.1111/EPI.17228
Abstract: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All s les were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger s le sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2019
DOI: 10.1101/525683
Abstract: Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected in iduals and 8,364 controls of European ancestry. We focused on three phenotypic groups the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, in iduals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABA A receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among in iduals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2 , and GABRG2 for GGE and LGI1, TRIM3 , and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.
Publisher: Wiley
Date: 04-07-2019
DOI: 10.1002/EPI4.12349
Publisher: Springer Science and Business Media LLC
Date: 17-05-2017
DOI: 10.1038/EJHG.2017.61
Publisher: Springer Science and Business Media LLC
Date: 09-03-2015
DOI: 10.1038/NG.3239
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 10-2021
Publisher: Elsevier BV
Date: 10-2014
Publisher: Cold Spring Harbor Laboratory
Date: 20-04-2021
DOI: 10.1101/2021.04.20.21255696
Abstract: De novo missense variants in KCNQ5 , encoding the voltage-gated K + channel K V 7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-cl recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling. We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) K V 7.5 or K V 7.5 and K V 7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The p.Arg359Cys variant altered PI(4,5)P 2 - interaction, presumably in the non-conducting preopen-closed state. Our study indicates that specific deleterious KCNQ5 variants are associated with GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional, rather than trafficking deficits. LOF of K V 7.5 channels will reduce the M-current, likely resulting in increased excitability of K V 7.5- expressing neurons. Further studies on a network level are necessary to understand which circuits are affected and how the variants induce generalized seizures.
Publisher: Elsevier BV
Date: 06-2019
Publisher: Elsevier BV
Date: 08-2018
Publisher: Wiley
Date: 15-01-2022
DOI: 10.1111/EPI.17166
Abstract: We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with in iduals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE. We performed a case–control whole exome sequencing study in unrelated in iduals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry‐matched controls. The association of ultra‐rare variants (URVs in 18 834 protein‐coding genes) with epilepsy was examined in 1928 in iduals with GGE (vs. 8578 controls), then separately in 945 in iduals with familial GGE (vs. 8626 controls), and finally in 1005 in iduals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ‐aminobutyric acid type A [GABA A ] receptors, 113 genes representing the GABAergic pathway). GABRG2 was associated with GGE ( p = 1.8 × 10 −5 ), approaching study‐wide significance in familial GGE ( p = 3.0 × 10 −6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABA A receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.9–7.8, false discovery rate [FDR]‐adjusted p = .0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3–6.7, FDR‐adjusted p = .022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3–2.5, FDR‐adjusted p = .0024) but not with sporadic GGE (OR = 1.3, 95% CI = .9–1.9, FDR‐adjusted p = .19). URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.
Publisher: Wiley
Date: 18-05-2021
DOI: 10.1111/EPI.16922
Abstract: Paroxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations. Confounding factors, including the heterogeneous etiology of epilepsies and medication effects, h er studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome‐wide association study (GWAS) on epilepsy ( n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG ( n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset ( n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses. Our analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations. Our results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.
Publisher: Wiley
Date: 31-08-2017
DOI: 10.1111/EPI.13871
Abstract: Mesial temporal lobe epilepsy with hippoc al sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS.
Publisher: Public Library of Science (PLoS)
Date: 30-01-2009
Publisher: Wiley
Date: 21-05-2021
DOI: 10.1002/ACN3.51374
Abstract: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of in iduals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. We performed exome sequencing of 1,128 in iduals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 in iduals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. We found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE. Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings.
Publisher: Public Library of Science (PLoS)
Date: 29-01-2010
Publisher: Public Library of Science (PLoS)
Date: 29-01-2010
Publisher: Springer Science and Business Media LLC
Date: 24-05-2021
DOI: 10.1038/S41431-021-00908-8
Abstract: While genetic studies of epilepsies can be performed in thousands of in iduals, phenotyping remains a manual, non-scalable task. A particular challenge is capturing the evolution of complex phenotypes with age. Here, we present a novel approach, applying phenotypic similarity analysis to a total of 3251 patient-years of longitudinal electronic medical record data from a previously reported cohort of 658 in iduals with genetic epilepsies. After mapping clinical data to the Human Phenotype Ontology, we determined the phenotypic similarity of in iduals sharing each genetic etiology within each 3-month age interval from birth up to a maximum age of 25 years. 140 of 600 (23%) of all 27 genes and 3-month age intervals with sufficient data for calculation of phenotypic similarity were significantly higher than expect by chance. 11 of 27 genetic etiologies had significant overall phenotypic similarity trajectories. These do not simply reflect strong statistical associations with single phenotypic features but appear to emerge from complex clinical constellations of features that may not be strongly associated in idually. As an attempt to reconstruct the cognitive framework of syndrome recognition in clinical practice, longitudinal phenotypic similarity analysis extends the traditional phenotyping approach by utilizing data from electronic medical records at a scale that is far beyond the capabilities of manual phenotyping. Delineation of how the phenotypic homogeneity of genetic epilepsies varies with age could improve the phenotypic classification of these disorders, the accuracy of prognostic counseling, and by providing historical control data, the design and interpretation of precision clinical trials in rare diseases.
Publisher: Springer Science and Business Media LLC
Date: 10-12-2018
DOI: 10.1038/S41467-018-07524-Z
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 in iduals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have erse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Publisher: Public Library of Science (PLoS)
Date: 23-07-2020
Publisher: Public Library of Science (PLoS)
Date: 21-05-2020
No related grants have been discovered for Roland Krause.