Publications by authors named "Michael Nothnagel"

111 Publications

Distinct gene-set burden patterns underlie common generalized and focal epilepsies.

EBioMedicine 2021 Sep 24;72:103588. Epub 2021 Sep 24.

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller Str. 27, Tübingen 72076, Germany. Electronic address:

Background: Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis.

Methods: The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls.

Findings: Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE.

Interpretation: Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies.

Funding: DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany).
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http://dx.doi.org/10.1016/j.ebiom.2021.103588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479647PMC
September 2021

Development and Evaluation of the Ancestry Informative Marker Panel of the VISAGE Basic Tool.

Genes (Basel) 2021 Aug 22;12(8). Epub 2021 Aug 22.

Forensic Genetics Unit, Institute of Forensic Sciences, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.

We detail the development of the ancestry informative single nucleotide polymorphisms (SNPs) panel forming part of the VISAGE Basic Tool (BT), which combines 41 appearance predictive SNPs and 112 ancestry predictive SNPs (three SNPs shared between sets) in one massively parallel sequencing (MPS) multiplex, whereas blood-based age analysis using methylation markers is run in a parallel MPS analysis pipeline. The selection of SNPs for the BT ancestry panel focused on established forensic markers that already have a proven track record of good sequencing performance in MPS, and the overall SNP multiplex scale closely matched that of existing forensic MPS assays. SNPs were chosen to differentiate individuals from the five main continental population groups of Africa, Europe, East Asia, America, and Oceania, extended to include differentiation of individuals from South Asia. From analysis of 1000 Genomes and HGDP-CEPH samples from these six population groups, the BT ancestry panel was shown to have no classification error using the Bayes likelihood calculators of the online analysis portal. The differentiation power of the component ancestry SNPs of BT was balanced as far as possible to avoid bias in the estimation of co-ancestry proportions in individuals with admixed backgrounds. The balancing process led to very similar cumulative population-specific divergence values for Africa, Europe, America, and Oceania, with East Asia being slightly below average, and South Asia an outlier from the other groups. Comparisons were made of the African, European, and Native American estimated co-ancestry proportions in the six admixed 1000 Genomes populations, using the BT ancestry panel SNPs and 572,000 Affymetrix Human Origins array SNPs. Very similar co-ancestry proportions were observed down to a minimum value of 10%, below which, low-level co-ancestry was not always reliably detected by BT SNPs. The analysis portal provides a comprehensive population dataset for the BT ancestry panel SNPs, comprising a 520-sample standardised reference dataset; 3445 additional samples from 1000 Genomes, HGDP-CEPH, Simons Foundation and Estonian Biocentre genome diversity projects; and 167 samples of six populations from in-house genotyping of individuals from Middle East, North and East African regions complementing those of the sampling regimes of the other diversity projects.
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http://dx.doi.org/10.3390/genes12081284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391248PMC
August 2021

Correction to: Towards a fine-scale picture of European genetic diversity.

Eur J Hum Genet 2021 Aug 19. Epub 2021 Aug 19.

Cologne Center for Genomics, University of Cologne, Cologne, Germany.

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http://dx.doi.org/10.1038/s41431-021-00949-zDOI Listing
August 2021

Analysis of single nucleotide polymorphisms in chronic beryllium disease.

Respir Res 2021 Apr 16;22(1):107. Epub 2021 Apr 16.

Department of Pneumology, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Killianstrasse 5, 79106, Freiburg, Germany.

Sarcoidosis and chronic beryllium disease (CBD) are phenocopies, however the latter one has a clear trigger factor that is beryllium exposure. This study analyses single nucleotide polymorphisms (SNPs) in a large cohort for beryllium-exposed persons. SNPs were chosen for their relevance in sarcoidosis. Even though one of largest cohorts of beryllium-exposed persons was analysed, no statistically relevant association between any SNP and CBD could be verified. Notably, some SNPs exhibit inverse OR for beryllium sensitization and CBD with nominally statistical significance, which allows hypothesizing about pathophysiological role of genes for the disease triggering and development.
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http://dx.doi.org/10.1186/s12931-021-01691-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051053PMC
April 2021

Evaluation of supervised machine-learning methods for predicting appearance traits from DNA.

Forensic Sci Int Genet 2021 07 23;53:102507. Epub 2021 Mar 23.

Cologne Center for Genomics, University of Cologne, Cologne, Germany; Faculty of Medicine and the Cologne University Hospital, Cologne, Germany. Electronic address:

The prediction of human externally visible characteristics (EVCs) based solely on DNA information has become an established approach in forensic and anthropological genetics in recent years. While for a large set of EVCs, predictive models have already been established using multinomial logistic regression (MLR), the prediction performances of other possible classification methods have not been thoroughly investigated thus far. Motivated by the question to identify a potential classifier that outperforms these specific trait models, we conducted a systematic comparison between the widely used MLR and three popular machine learning (ML) classifiers, namely support vector machines (SVM), random forest (RF) and artificial neural networks (ANN), that have shown good performance outside EVC prediction. As examples, we used eye, hair and skin color categories as phenotypes and genotypes based on the previously established IrisPlex, HIrisPlex, and HIrisPlex-S DNA markers. We compared and assessed the performances of each of the four methods, complemented by detailed hyperparameter tuning that was applied to some of the methods in order to maximize their performance. Overall, we observed that all four classification methods showed rather similar performance, with no method being substantially superior to the others for any of the traits, although performances varied slightly across the different traits and more so across the trait categories. Hence, based on our findings, none of the ML methods applied here provide any advantage on appearance prediction, at least when it comes to the categorical pigmentation traits and the selected DNA markers used here.
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http://dx.doi.org/10.1016/j.fsigen.2021.102507DOI Listing
July 2021

Exome sequencing utility in defining the genetic landscape of hearing loss and novel-gene discovery in Iran.

Clin Genet 2021 07 24;100(1):59-78. Epub 2021 Mar 24.

Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

Hearing loss (HL) is one of the most common sensory defects affecting more than 466 million individuals worldwide. It is clinically and genetically heterogeneous with over 120 genes causing non-syndromic HL identified to date. Here, we performed exome sequencing (ES) on a cohort of Iranian families with no disease-causing variants in known deafness-associated genes after screening with a targeted gene panel. We identified likely causal variants in 20 out of 71 families screened. Fifteen families segregated variants in known deafness-associated genes. Eight families segregated variants in novel candidate genes for HL: DBH, TOP3A, COX18, USP31, TCF19, SCP2, TENM1, and CARMIL1. In the three of these families, intrafamilial locus heterogeneity was observed with variants in both known and novel candidate genes. In aggregate, we were able to identify the underlying genetic cause of HL in nearly 30% of our study cohort using ES. This study corroborates the observation that high-throughput DNA sequencing in populations with high rates of consanguineous marriages represents a more appropriate strategy to elucidate the genetic etiology of heterogeneous conditions such as HL.
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http://dx.doi.org/10.1111/cge.13956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195868PMC
July 2021

Testing the impact of trait prevalence priors in Bayesian-based genetic prediction modeling of human appearance traits.

Forensic Sci Int Genet 2021 01 4;50:102412. Epub 2020 Nov 4.

Cologne Center for Genomics, University of Cologne, Cologne, Germany; University Hospital Cologne, Cologne, Germany. Electronic address:

The prediction of appearance traits by use of solely genetic information has become an established approach and a number of statistical prediction models have already been developed for this purpose. However, given limited knowledge on appearance genetics, currently available models are incomplete and do not include all causal genetic variants as predictors. Therefore such prediction models may benefit from the inclusion of additional information that acts as a proxy for this unknown genetic background. Use of priors, possibly informed by trait category prevalence values in biogeographic ancestry groups, in a Bayesian framework may thus improve the prediction accuracy of previously predicted externally visible characteristics, but has not been investigated as of yet. In this study, we assessed the impact of using trait prevalence-informed priors on the prediction performance in Bayesian models for eye, hair and skin color as well as hair structure and freckles in comparison to the respective prior-free models. Those prior-free models were either similarly defined either very close to the already established ones by using a reduced predictive marker set. However, these differences in the number of the predictive markers should not affect significantly our main outcomes. We observed that such priors often had a strong effect on the prediction performance, but to varying degrees between different traits and also different trait categories, with some categories barely showing an effect. While we found potential for improving the prediction accuracy of many of the appearance trait categories tested by using priors, our analyses also showed that misspecification of those prior values often severely diminished the accuracy compared to the respective prior-free approach. This emphasizes the importance of accurate specification of prevalence-informed priors in Bayesian prediction modeling of appearance traits. However, the existing literature knowledge on spatial prevalence is sparse for most appearance traits, including those investigated here. Due to the limitations in appearance trait prevalence knowledge, our results render the use of trait prevalence-informed priors in DNA-based appearance trait prediction currently infeasible.
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http://dx.doi.org/10.1016/j.fsigen.2020.102412DOI Listing
January 2021

A Y-chromosomal survey of Ecuador's multi-ethnic population reveals new insights into the tri-partite population structure and supports an early Holocene age of the rare Native American founder lineage C3-MPB373.

Forensic Sci Int Genet 2021 03 16;51:102427. Epub 2020 Nov 16.

Department of Forensic Genetics, Institute of Legal Medicine and Forensic Sciences, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Ecuador is a multiethnic and pluricultural country with a complex history defined by migration and admixture processes. The present study aims to increase our knowledge on the Ecuadorian Native Amerindian groups and the unique South American Y-chromosome haplogroup C3-MPB373 through the analysis of up to 23 Y-chromosome STRs (Y-STRs) and several Y-SNPs in a sample of 527 Ecuadorians from 7 distinct populations and geographic areas, including Kichwa and non-Kichwa Native Amerindians, Mestizos and Afro-Ecuadorians. Our results reveal the presence of C3-MPB373 both in the Amazonian lowland Kichwa with frequencies up to 28 % and, for the first time, in notable proportions in Kichwa populations from the Ecuadorian highlands. The substantially higher frequencies of C3-MPB373 in the Amazonian lowlands found in Kichwa and Waorani individuals suggest a founder effect in that area. Notably, estimates for the time to the most recent common ancestor (TMRCA) in the range of 7.2-9.0 kya point to an ancient origin of the haplogroup and suggest an early Holocene expansion of C3-MPB373 into South America. Finally, the pairwise genetic distances (R) separate the Kichwa Salasaka from all the other Native Amerindian and Ecuadorian groups, indicating a so far hidden diversity among the Kichwa-speaking populations and suggesting a more southern origin of this population. In sum, our study provides a more in-depth knowledge of the male genetic structure of the multiethnic Ecuadorian population, as well as a valuable reference dataset for forensic use.
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http://dx.doi.org/10.1016/j.fsigen.2020.102427DOI Listing
March 2021

Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits.

Nat Commun 2020 11 3;11(1):5562. Epub 2020 Nov 3.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany.

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (r = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.
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http://dx.doi.org/10.1038/s41467-020-19265-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642344PMC
November 2020

The impact of correlations between pigmentation phenotypes and underlying genotypes on genetic prediction of pigmentation traits.

Forensic Sci Int Genet 2021 01 24;50:102395. Epub 2020 Sep 24.

Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China. Electronic address:

Predicting appearance phenotypes from genotypes is relevant for various areas of human genetic research and applications such as genetic epidemiology, human history, anthropology, and particularly in forensics. Many appearance phenotypes, and thus their underlying genotypes, are highly correlated, with pigmentation traits serving as primary examples. However, all available genetic prediction models, including those for pigmentation traits currently used in forensic DNA phenotyping, ignore phenotype correlations. Here, we investigated the impact of appearance phenotype correlations on genetic appearance prediction in the exemplary case of three pigmentation traits. We used data for categorical eye, hair and skin colour as well as 41 DNA markers utilized in the recently established HIrisPlex-S system from 762 individuals with complete phenotype and genotype information. Based on these data, we performed genetic prediction modelling of eye, hair and skin colour via three different strategies, namely the established approach of predicting phenotypes solely based on genotypes while not considering phenotype correlations, and two novel approaches that considered phenotype correlations, either incorporating truly observed correlated phenotypes or DNA-predicted correlated phenotypes in addition to the DNA predictors. We found that using truly observed correlated pigmentation phenotypes as additional predictors increased the DNA-based prediction accuracies for almost all eye, hair and skin colour categories, with the largest increase for intermediate eye colour, brown hair colour, dark to black skin colour, and particularly for dark skin colour. Outcomes of dedicated computer simulations suggest that this prediction accuracy increase is due to the additional genetic information that is implicitly provided by the truly observed correlated pigmentation phenotypes used, yet not covered by the DNA predictors applied. In contrast, considering DNA-predicted correlated pigmentation phenotypes as additional predictors did not improve the performance of the genetic prediction of eye, hair and skin colour, which was in line with the results from our computer simulations. Hence, in practical applications of DNA-based appearance prediction where no phenotype knowledge is available, such as in forensic DNA phenotyping, it is not advised to use DNA-predicted correlated phenotypes as predictors in addition to the DNA predictors. In the very least, this is not recommended for the pigmentation traits and the established pigmentation DNA predictors tested here.
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http://dx.doi.org/10.1016/j.fsigen.2020.102395DOI Listing
January 2021

The exhaustive genomic scan approach, with an application to rare-variant association analysis.

Eur J Hum Genet 2020 09 15;28(9):1283-1291. Epub 2020 May 15.

Faculty of Medicine and University Hospital Cologne, Cologne Center for Genomics (CCG), University of Cologne, Weyertal 115b, 50931, Cologne, Germany.

Region-based genome-wide scans are usually performed by use of a priori chosen analysis regions. Such an approach will likely miss the region comprising the strongest signal and, thus, may result in increased type II error rates and decreased power. Here, we propose a genomic exhaustive scan approach that analyzes all possible subsequences and does not rely on a prior definition of the analysis regions. As a prime instance, we present a computationally ultraefficient implementation using the rare-variant collapsing test for phenotypic association, the genomic exhaustive collapsing scan (GECS). Our implementation allows for the identification of regions comprising the strongest signals in large, genome-wide rare-variant association studies while controlling the family-wise error rate via permutation. Application of GECS to two genomic data sets revealed several novel significantly associated regions for age-related macular degeneration and for schizophrenia. Our approach also offers a high potential to improve genome-wide scans for selection, methylation, and other analyses.
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http://dx.doi.org/10.1038/s41431-020-0639-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608423PMC
September 2020

Towards a fine-scale picture of European genetic diversity.

Eur J Hum Genet 2020 07 1;28(7):851-852. Epub 2020 Apr 1.

Cologne Center for Genomics, University of Cologne, Cologne, Germany.

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http://dx.doi.org/10.1038/s41431-020-0620-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316748PMC
July 2020

Special issue on 'Genetic epidemiology of complex diseases: impact of population history and modelling assumptions'.

Hum Genet 2020 01;139(1):1-3

Cologne Center for Genomics, University of Cologne, Cologne, Germany.

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http://dx.doi.org/10.1007/s00439-019-02074-wDOI Listing
January 2020

A Rare Variant Nonparametric Linkage Method for Nuclear and Extended Pedigrees with Application to Late-Onset Alzheimer Disease via WGS Data.

Am J Hum Genet 2019 10;105(4):822-835

Center for Statistical Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Taub Institute on Alzheimer Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University, New York, NY 10027, USA; Center for Statistical Genetics, Columbia University, New York, NY 10027, USA. Electronic address:

To analyze family-based whole-genome sequence (WGS) data for complex traits, we developed a rare variant (RV) non-parametric linkage (NPL) analysis method, which has advantages over association methods. The RV-NPL differs from the NPL in that RVs are analyzed, and allele sharing among affected relative-pairs is estimated only for minor alleles. Analyzing families can increase power because causal variants with familial aggregation usually have larger effect sizes than those underlying sporadic diseases. Differing from association analysis, for NPL only affected individuals are analyzed, which can increase power, since unaffected family members can be susceptibility variant carriers. RV-NPL is robust to population substructure and admixture, inclusion of nonpathogenic variants, as well as allelic and locus heterogeneity and can readily be applied outside of coding regions. In contrast to analyzing common variants using NPL, where loci localize to large genomic regions (e.g., >50 Mb), mapped regions are well defined for RV-NPL. Using simulation studies, we demonstrate that RV-NPL is substantially more powerful than applying traditional NPL methods to analyze RVs. The RV-NPL was applied to analyze 107 late-onset Alzheimer disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with WGS data, and statistically significant linkage (LOD ≥ 3.8) was found with RVs in PSMF1 and PTPN21 which have been shown to be involved in LOAD etiology. Additionally, nominally significant linkage was observed with RVs in ABCA7, ACE, EPHA1, and SORL1, genes that were previously reported to be associated with LOAD. RV-NPL is an ideal method to elucidate the genetic etiology of complex familial diseases.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817540PMC
October 2019

Distinct genetic variation and heterogeneity of the Iranian population.

PLoS Genet 2019 09 24;15(9):e1008385. Epub 2019 Sep 24.

Cologne Center for Genomics, University of Cologne, Cologne, Germany.

Iran, despite its size, geographic location and past cultural influence, has largely been a blind spot for human population genetic studies. With only sparse genetic information on the Iranian population available, we pursued its genome-wide and geographic characterization based on 1021 samples from eleven ethnic groups. We show that Iranians, while close to neighboring populations, present distinct genetic variation consistent with long-standing genetic continuity, harbor high heterogeneity and different levels of consanguinity, fall apart into a cluster of similar groups and several admixed ones and have experienced numerous language adoption events in the past. Our findings render Iran an important source for human genetic variation in Western and Central Asia, will guide adequate study sampling and assist the interpretation of putative disease-implicated genetic variation. Given Iran's internal genetic heterogeneity, future studies will have to consider ethnic affiliations and possible admixture.
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http://dx.doi.org/10.1371/journal.pgen.1008385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759149PMC
September 2019

Missense variants in NOX1 and p22phox in a case of very-early-onset inflammatory bowel disease are functionally linked to NOD2.

Cold Spring Harb Mol Case Stud 2019 02 1;5(1). Epub 2019 Feb 1.

Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany.

Whole-genome and whole-exome sequencing of individual patients allow the study of rare and potentially causative genetic variation. In this study, we sequenced DNA of a trio comprising a boy with very-early-onset inflammatory bowel disease (veoIBD) and his unaffected parents. We identified a rare, X-linked missense variant in the NAPDH oxidase gene (c.C721T, p.R241C) in heterozygous state in the mother and in hemizygous state in the patient. We discovered that, in addition, the patient was homozygous for a common missense variant in the gene (c.T214C, p.Y72H). encodes the p22phox protein, a cofactor for NOX1. Functional assays revealed reduced cellular ROS generation and antibacterial capacity of NOX1 and p22phox variants in intestinal epithelial cells. Moreover, the identified NADPH oxidase complex variants affected NOD2-mediated immune responses, and p22phox was identified as a novel NOD2 interactor. In conclusion, we detected missense variants in a veoIBD patient that disrupt the host response to bacterial challenges and reduce protective innate immune signaling via NOD2. We assume that the patient's individual genetic makeup favored disturbed intestinal mucosal barrier function.
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http://dx.doi.org/10.1101/mcs.a002428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371741PMC
February 2019

Unsupported claim of significant discrimination between monozygotic twins from multiple pairs based on three age-related DNA methylation markers.

Forensic Sci Int Genet 2019 03 9;39:e1-e2. Epub 2019 Jan 9.

Cologne Center for Genomics, University of Cologne, Cologne, Germany.

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http://dx.doi.org/10.1016/j.fsigen.2019.01.003DOI Listing
March 2019

True colors: A literature review on the spatial distribution of eye and hair pigmentation.

Forensic Sci Int Genet 2019 03 2;39:109-118. Epub 2019 Jan 2.

Cologne Center for Genomics, University of Cologne, Cologne, Germany. Electronic address:

DNA-based prediction of externally visible characteristics has become an established approach in forensic genetics, with the aim of tracing individuals who are potentially unknown to the investigating authorities but without using this prediction as evidence in court. While a number of prediction models have been proposed, use of prior probabilities in those models has largely been absent. Here, we aim at compiling information on the spatial distribution of eye and hair coloration in order to use this as prior knowledge to improve prediction accuracy. To this end, we conducted a detailed literature review and created maps showing the eye and hair pigmentation prevalence both by countries with available information and by interpolation in order to obtain prior estimates for populations without available data. Furthermore, we assessed the association between these two traits in a very large data set. A strong limitation was the quite low amount of available data, especially outside Europe. We hope that our results will facilitate the improvement of already existing and of novel prediction methods for pigmentation traits and induce further studies on the spatial distribution of these traits.
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http://dx.doi.org/10.1016/j.fsigen.2019.01.001DOI Listing
March 2019

Guideline-based and bioinformatic reassessment of lesion-associated gene and variant pathogenicity in focal human epilepsies.

Epilepsia 2018 11 20;59(11):2145-2152. Epub 2018 Oct 20.

Cologne Center for Genomics, University of Cologne, Cologne, Germany.

Objective: Increasing availability of surgically resected brain tissue from patients with focal epilepsy and focal cortical dysplasia or low-grade glioneuronal tumors has fostered large-scale genetic examination. However, assessment of pathogenicity of germ line and somatic variants remains difficult. Here, we present a state-of-the-art evaluation of reported genes and variants associated with epileptic brain lesions.

Methods: We critically reevaluated the pathogenicity for all neuropathology-associated variants reported to date in the PubMed and ClinVar databases, including 101 neuropathology-associated missense variants encompassing 11 disease-related genes. We assessed gene variant tolerance and classified all identified missense variants according to guidelines from the American College of Medical Genetics and Genomics (ACMG). We further extended the bioinformatic variant prediction by introducing a novel gene-specific deleteriousness ranking for prediction scores.

Results: Application of ACMG guidelines and in silico gene variant tolerance analysis classified only seven of 11 genes to be likely disease-associated according to the reported disease mechanism, whereas 61 (60.4%) of 101 variants of those genes were classified as of uncertain significance, 37 (36.6%) as being likely pathogenic, and 3 (3%) as being pathogenic.

Significance: We concluded that the majority of neuropathology-associated variants reported to date do not have enough evidence to be classified as pathogenic. Interpretation of lesion-associated variants remains challenging, and application of current ACMG guidelines is recommended for interpretation and prediction.
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http://dx.doi.org/10.1111/epi.14579DOI Listing
November 2018

Evaluation of potential effects of Plastin 3 overexpression and low-dose SMN-antisense oligonucleotides on putative biomarkers in spinal muscular atrophy mice.

PLoS One 2018 6;13(9):e0203398. Epub 2018 Sep 6.

Institute of Human Genetics, University of Cologne, Cologne, Germany.

Objectives: Spinal muscular atrophy (SMA) is a devastating motor neuron disorder caused by homozygous loss of the survival motor neuron 1 (SMN1) gene and insufficient functional SMN protein produced by the SMN2 copy gene. Additional genetic protective modifiers such as Plastin 3 (PLS3) can counteract SMA pathology despite insufficient SMN protein. Recently, Spinraza, an SMN antisense oligonucleotide (ASO) that restores full-length SMN2 transcripts, has been FDA- and EMA-approved for SMA therapy. Hence, the availability of biomarkers allowing a reliable monitoring of disease and therapy progression would be of great importance. Our objectives were (i) to analyse the feasibility of SMN and of six SMA biomarkers identified by the BforSMA study in the Taiwanese SMA mouse model, (ii) to analyse the effect of PLS3 overexpression on these biomarkers, and (iii) to assess the impact of low-dose SMN-ASO therapy on the level of SMN and the six biomarkers.

Methods: At P10 and P21, the level of SMN and six putative biomarkers were compared among SMA, heterozygous and wild type mice, with or without PLS3 overexpression, and with or without presymptomatic low-dose SMN-ASO subcutaneous injection. SMN levels were measured in whole blood by ECL immunoassay and of six SMA putative biomarkers, namely Cartilage Oligomeric Matrix Protein (COMP), Dipeptidyl Peptidase 4 (DPP4), Tetranectin (C-type Lectin Family 3 Member B, CLEC3B), Osteopontin (Secreted Phosphoprotein 1, SPP1), Vitronectin (VTN) and Fetuin A (Alpha 2-HS Glycoprotein, AHSG) in plasma.

Results: SMN levels were significantly discernible between SMA, heterozygous and wild type mice. However, no significant differences were measured upon low-dose SMN-ASO treatment compared to untreated animals. Of the six biomarkers, only COMP and DPP4 showed high and SPP1 moderate correlation with the SMA phenotype. PLS3 overexpression neither influenced the SMN level nor the six biomarkers, supporting the hypothesis that PLS3 acts as an independent protective modifier.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203398PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126849PMC
February 2019

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Gut 2019 06 1;68(6):1099-1107. Epub 2018 Aug 1.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Objective: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.

Design: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.

Results: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).

Conclusion: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
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http://dx.doi.org/10.1136/gutjnl-2018-316228DOI Listing
June 2019

Rare coding variants in genes encoding GABA receptors in genetic generalised epilepsies: an exome-based case-control study.

Lancet Neurol 2018 08 17;17(8):699-708. Epub 2018 Jul 17.

Background: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.

Methods: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABA receptors and was compared to the respective GABA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.

Findings: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; p=0·0014, adjusted p=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; p=0·0081, adjusted p=0·016). Comparison of genes encoding GABA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; p=0·013, adjusted p=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.

Interpretation: Functionally relevant variants in genes encoding GABA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.

Funding: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).
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http://dx.doi.org/10.1016/S1474-4422(18)30215-1DOI Listing
August 2018

Ancient DNA study reveals HLA susceptibility locus for leprosy in medieval Europeans.

Nat Commun 2018 05 1;9(1):1569. Epub 2018 May 1.

Institute of Clinical Molecular Biology, Kiel University, Kiel, 24105, Germany.

Leprosy, a chronic infectious disease caused by Mycobacterium leprae (M. leprae), was very common in Europe till the 16th century. Here, we perform an ancient DNA study on medieval skeletons from Denmark that show lesions specific for lepromatous leprosy (LL). First, we test the remains for M. leprae DNA to confirm the infection status of the individuals and to assess the bacterial diversity. We assemble 10 complete M. leprae genomes that all differ from each other. Second, we evaluate whether the human leukocyte antigen allele DRB1*15:01, a strong LL susceptibility factor in modern populations, also predisposed medieval Europeans to the disease. The comparison of genotype data from 69 M. leprae DNA-positive LL cases with those from contemporary and medieval controls reveals a statistically significant association in both instances. In addition, we observe that DRB1*15:01 co-occurs with DQB1*06:02 on a haplotype that is a strong risk factor for inflammatory diseases today.
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http://dx.doi.org/10.1038/s41467-018-03857-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931558PMC
May 2018

Performance of in silico prediction tools for the classification of rare BRCA1/2 missense variants in clinical diagnostics.

BMC Med Genomics 2018 03 27;11(1):35. Epub 2018 Mar 27.

Center for Familial Breast and Ovarian Cancer, Center for Integated Oncology (CIO), Medical Faculty, University Hospital Cologne, Kerpener Straße 34, Cologne, 50931, Germany.

Background: The use of next-generation sequencing approaches in clinical diagnostics has led to a tremendous increase in data and a vast number of variants of uncertain significance that require interpretation. Therefore, prediction of the effects of missense mutations using in silico tools has become a frequently used approach. Aim of this study was to assess the reliability of in silico prediction as a basis for clinical decision making in the context of hereditary breast and/or ovarian cancer.

Methods: We tested the performance of four prediction tools (Align-GVGD, SIFT, PolyPhen-2, MutationTaster2) using a set of 236 BRCA1/2 missense variants that had previously been classified by expert committees. However, a major pitfall in the creation of a reliable evaluation set for our purpose is the generally accepted classification of BRCA1/2 missense variants using the multifactorial likelihood model, which is partially based on Align-GVGD results. To overcome this drawback we identified 161 variants whose classification is independent of any previous in silico prediction. In addition to the performance as stand-alone tools we examined the sensitivity, specificity, accuracy and Matthews correlation coefficient (MCC) of combined approaches.

Results: PolyPhen-2 achieved the lowest sensitivity (0.67), specificity (0.67), accuracy (0.67) and MCC (0.39). Align-GVGD achieved the highest values of specificity (0.92), accuracy (0.92) and MCC (0.73), but was outperformed regarding its sensitivity (0.90) by SIFT (1.00) and MutationTaster2 (1.00). All tools suffered from poor specificities, resulting in an unacceptable proportion of false positive results in a clinical setting. This shortcoming could not be bypassed by combination of these tools. In the best case scenario, 138 families would be affected by the misclassification of neutral variants within the cohort of patients of the German Consortium for Hereditary Breast and Ovarian Cancer.

Conclusion: We show that due to low specificities state-of-the-art in silico prediction tools are not suitable to predict pathogenicity of variants of uncertain significance in BRCA1/2. Thus, clinical consequences should never be based solely on in silico forecasts. However, our data suggests that SIFT and MutationTaster2 could be suitable to predict benignity, as both tools did not result in false negative predictions in our analysis.
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http://dx.doi.org/10.1186/s12920-018-0353-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870501PMC
March 2018

Pathway-induced allelic spectra of diseases in the presence of strong genetic effects.

Hum Genet 2018 Mar 8;137(3):215-230. Epub 2018 Feb 8.

Department of Statistical Genetics and Bioinformatics, Cologne Center for Genomics, University of Cologne, Weyertal 115b, 50931, Cologne, Germany.

Complex diseases are frequently modeled as following an additive model that excludes both intra- and inter-locus interaction, while at the same time reports on non-additive biological structures are ample, prominently featuring numerous metabolic and signaling pathways. Using extensive forward population simulations, we explored the impact of three basic pathway motifs on the relationship between epidemiological parameters, including disease prevalence, relative risk, sibling recurrence risk as well as causal variant number and allele frequency. We found that some but not all pathway motifs can shift the relationships between these parameters in comparison to the classical additive liability threshold model. The strongest deviations were observed with linear, cascade-like motifs that form an integral part of many reported pathways. We also modeled maturity-onset diabetes of the young (MODY) as a combination of different basic pathway motifs and observed a good concordance in epidemiological parameter values between our simulated data under this model and those reported in the literature. Given the widespread nature of pathways, including those in the etiology of human diseases, our results re-emphasize the need for non-additive interaction modeling of genetic variants to become an additional standard approach in analyzing human genetic data.
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http://dx.doi.org/10.1007/s00439-018-1872-5DOI Listing
March 2018

Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.

Eur J Hum Genet 2018 02 22;26(2):258-264. Epub 2018 Jan 22.

Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.

Rolandic epilepsy (RE) is the most common focal epilepsy in childhood. To date no hypothesis-free exome-wide mutational screen has been conducted for RE and atypical RE (ARE). Here we report on whole-exome sequencing of 194 unrelated patients with RE/ARE and 567 ethnically matched population controls. We identified an exome-wide significantly enriched burden for deleterious and loss-of-function variants only for the established RE/ARE gene GRIN2A. The statistical significance of the enrichment disappeared after removing ARE patients. For several disease-related gene-sets, an odds ratio >1 was detected for loss-of-function variants.
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http://dx.doi.org/10.1038/s41431-017-0034-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839048PMC
February 2018

Publisher Correction: Identification and characterization of two functional variants in the human longevity gene FOXO3.

Nat Commun 2018 01 17;9(1):320. Epub 2018 Jan 17.

Department of Statistical Genetics and Bioinformatics, Cologne Center for Genomics, University of Cologne, Weyertal 115b, 50931, Cologne, Germany.

The original version of this Article contained an error in the spelling of the author Robert Häsler, which was incorrectly given as Robert Häesler. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-02842-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770466PMC
January 2018

Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling.

Eur J Hum Genet 2018 02 10;26(2):197-209. Epub 2018 Jan 10.

Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.

Acrocallosal syndrome (ACLS) is an autosomal recessive neurodevelopmental disorder caused by KIF7 defects and belongs to the heterogeneous group of ciliopathies related to Joubert syndrome (JBTS). While ACLS is characterized by macrocephaly, prominent forehead, depressed nasal bridge, and hypertelorism, facial dysmorphism has not been emphasized in JBTS cohorts with molecular diagnosis. To evaluate the specificity and etiology of ACLS craniofacial features, we performed whole exome or targeted Sanger sequencing in patients with the aforementioned overlapping craniofacial appearance but variable additional ciliopathy features followed by functional studies. We found (likely) pathogenic variants of KIF7 in 5 out of 9 families, including the original ACLS patients, and delineated 1000 to 4000-year-old Swiss founder alleles. Three of the remaining families had (likely) pathogenic variants in the JBTS gene C5orf42, and one patient had a novel de novo frameshift variant in SHH known to cause autosomal dominant holoprosencephaly. In accordance with the patients' craniofacial anomalies, we showed facial midline widening after silencing of C5orf42 in chicken embryos. We further supported the link between KIF7, SHH, and C5orf42 by demonstrating abnormal primary cilia and diminished response to a SHH agonist in fibroblasts of C5orf42-mutated patients, as well as axonal pathfinding errors in C5orf42-silenced chicken embryos similar to those observed after perturbation of Shh signaling. Our findings, therefore, suggest that beside the neurodevelopmental features, macrocephaly and facial widening are likely more general signs of disturbed SHH signaling. Nevertheless, long-term follow-up revealed that C5orf42-mutated patients showed catch-up development and fainting of facial features contrary to KIF7-mutated patients.
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http://dx.doi.org/10.1038/s41431-017-0019-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839020PMC
February 2018

Identification and characterization of two functional variants in the human longevity gene FOXO3.

Nat Commun 2017 12 12;8(1):2063. Epub 2017 Dec 12.

Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Rosalind-Franklin-Straße 12, 24105, Kiel, Germany.

FOXO3 is consistently annotated as a human longevity gene. However, functional variants and underlying mechanisms for the association remain unknown. Here, we perform resequencing of the FOXO3 locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two FOXO3 SNVs, rs12206094 and rs4946935, to be most significantly associated with longevity and further characterize them functionally. We experimentally validate the in silico predicted allele-dependent binding of transcription factors (CTCF, SRF) to the SNVs. Specifically, in luciferase reporter assays, the longevity alleles of both variants show considerable enhancer activities that are reversed by IGF-1 treatment. An eQTL database search reveals that the alleles are also associated with higher FOXO3 mRNA expression in various human tissues, which is in line with observations in long-lived model organisms. In summary, we present experimental evidence for a functional link between common intronic variants in FOXO3 and human longevity.
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http://dx.doi.org/10.1038/s41467-017-02183-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727304PMC
December 2017

A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis.

Am J Hum Genet 2017 Sep;101(3):417-427

Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Botnar Research Centre, Windmill Road, Oxford OX3 7HE, UK; Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK; NIHR Biomedical Research Centre, NDORMS, University of Oxford, Botnar Research Centre, Windmill Road, Oxford OX3 7HE, UK. Electronic address:

Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10. As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research.
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http://dx.doi.org/10.1016/j.ajhg.2017.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591021PMC
September 2017
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