Michael Krawczak

University of Zurich, Zürich, Zurich, Switzerland

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Publications (360)2171.48 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Match probability calculation is deemed much more intricate for lineage genetic markers, including Y-chromosomal short tandem repeats (Y-STRs), than for autosomal markers. This is because, owing to the lack of recombination, strong interdependence between markers is likely, which implies that haplotype frequency estimates cannot simply be obtained through the multiplication of allele frequency estimates. As yet, however, the practical relevance of this problem has not been studied in much detail using real data. In fact, such scrutiny appears well warranted because the high mutation rates of Y-STRs and the possibility of backward mutation should have worked against the statistical association of Y-STRs. We examined haplotype data of 21 markers included in the PowerPlex(®)Y23 set (PPY23, Promega Corporation, Madison, WI) originating from six different populations (four European and two Asian). Assessing the conditional entropies of the markers, given different subsets of markers from the same panel, we demonstrate that the PowerPlex(®)Y23 set cannot be decomposed into smaller marker subsets that would be (conditionally) independent. Nevertheless, in all six populations, >94% of the joint entropy of the 21 markers is explained by the seven most rapidly mutating markers. Although this result might render a reduction in marker number a sensible option for practical casework, the partial haplotypes would still be almost as diverse as the full haplotypes. Therefore, match probability calculation remains difficult and calls for the improvement of currently available methods of haplotype frequency estimation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Forensic science international. Genetics. 10/2014;
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    ABSTRACT: In a worldwide collaborative effort, 19,630 Y-chromosomes were sampled from 129 different populations in 51 countries. These chromosomes were typed for 23 short-tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, GATAH4, DYS481, DYS533, DYS549, DYS570, DYS576, DYS643) and using the PowerPlex Y23 System (PPY23, Promega Corporation, Madison, WI). Locus-specific allelic spectra of these markers were determined and a consistently high level of allelic diversity was observed. A considerable number of null, duplicate and off-ladder alleles were revealed. Standard single-locus and haplotype-based parameters were calculated and compared between subsets of Y-STR markers established for forensic casework. The PPY23 marker set provides substantially stronger discriminatory power than other available kits but at the same time reveals the same general patterns of population structure as other marker sets. A strong correlation was observed between the number of Y-STRs included in a marker set and some of the forensic parameters under study. Interestingly a weak but consistent trend towards smaller genetic distances resulting from larger numbers of markers became apparent.
    Forensic Science International: Genetics 04/2014; 12:12-23. · 3.86 Impact Factor
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    ABSTRACT: Genome wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention.Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2, Chr2p14) in recent GWAS, and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden.Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (p=1.02×10(-5)) in the German cohort with genotypic odds ratios of 3.56 [95% CI 1.29-9.77] for CG heterozygotes and 5.38 [2.39-12.10] for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (p=0.014; ORallelic=1.82 [1.12-2.95] but not in Swedish patients. Posthoc combined analyses of German/Swiss/Austrian patients with available liver histology (N=244, p=0.00014, ORallelic=2.84) and of males only (N=431, p=2.17×10(-5), ORallelic=2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH.PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.
    Human Molecular Genetics 02/2014; · 7.69 Impact Factor
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    ABSTRACT: Next Generation Sequencing (NGS) of whole exomes or genomes is increasingly being used in human genetic research and diagnostics. Sharing NGS data with third parties can help physicians and researchers to identify causative or predisposing mutations for a specific sample of interest more efficiently. In many cases, however, the exchange of such data may collide with data privacy regulations. GrabBlur is a newly developed tool to aggregate and share NGS-derived single nucleotide variant (SNV) data in a public database, keeping individual samples unidentifiable. In contrast to other currently existing SNV databases, GrabBlur includes phenotypic information and contact details of the submitter of a given database entry. By means of GrabBlur human geneticists can securely and easily share SNV data from resequencing projects. GrabBlur can ease the interpretation of SNV data by offering basic annotations, genotype frequencies and in particular phenotypic information -given that this information was shared -for the SNV of interest. Tool description: GrabBlur facilitates the combination of phenotypic and NGS data (VCF files) via a local interface or command line operations. Data submissions may include HPO (Human Phenotype Ontology) terms, other trait descriptions, NGS technology information and the identity of the submitter. Most of this information is optional and its provision at the discretion of the submitter. Upon initial intake, GrabBlur merges and aggregates all sample-specific data. If a certain SNV is rare, the sample-specific information is replaced with the submitter identity. Generally, all data in GrabBlur are highly aggregated so that they can be shared with others while ensuring maximum privacy. Thus, it is impossible to reconstruct complete exomes or genomes from the database or to re-identify single individuals. After the individual information has been sufficiently "blurred", the data can be uploaded into a publicly accessible domain where aggregated genotypes are provided alongside phenotypic information. A web interface allows querying the database and the extraction of gene-wise SNV information. If an interesting SNV is found, the interrogator can get in contact with the submitter to exchange further information on the carrier and clarify, for example, whether the latter's phenotype matches with phenotype of their own patient.
    BMC genomics. 01/2014; 15 Suppl 4.
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    ABSTRACT: In a worldwide collaborative effort, 19,630 Y-chromosomes were sampled from 129 different populations in 51 countries. These chromosomes were typed for 23 short-tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, GATAH4, DYS481, DYS533, DYS549, DYS570, DYS576, DYS643) and using the PowerPlex Y23 System (PPY23, Promega Corporation, Madison, WI). Locus-specific allelic spectra of these markers were determined and a consistently high level of allelic diversity was observed. A considerable number of null, duplicate and off-ladder alleles were revealed. Standard single-locus and haplotype-based parameters were calculated and compared between subsets of Y-STR markers established for forensic casework. The PPY23 marker set provides substantially stronger discriminatory power than other available kits but at the same time reveals the same general patterns of population structure as other marker sets. A strong correlation was observed between the number of Y-STRs included in a marker set and some of the forensic parameters under study. Interestingly a weak but consistent trend towards smaller genetic distances resulting from larger numbers of markers became apparent.
    Forensic Science International: Genetics 01/2014; · 3.86 Impact Factor
  • Carolin Knecht, Michael Krawczak
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    ABSTRACT: Databases of disease-associated or disease-causing mutations allow the study, not only of the molecular mechanisms underlying the primary lesions at the DNA level, but also of the functional consequences of mutation at the phenotypic level. The Human Gene Mutation Database (HGMD) and the bioinformatics analyses of its content provide an illustrative example of this indirect approach to molecular genetic epidemiology. In fact, the Bayesian type of reasoning underlying previous scientific analyses of HGMD data is also reflected in current software tools used to predict the likely disease relevance of a newly detected genetic variant. After a brief resume of the past scientific utility of HGMD, we, therefore, shortly review three representative and commonly used examples of these tools, namely SIFT, PolyPhen-2 and NNSplice.
    Human Genetics 11/2013; · 4.63 Impact Factor
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    ABSTRACT: Colorectal cancer (CRC) is one of the most common cancer worldwide. However, a large number of genetic risk factors involved in CRC have not been understood. Copy number variations (CNVs) might partly contribute to the 'missing heritability' of CRC. An increased overall burden of CNV has been identified in several complex diseases, whereas the association between the overall CNV burden and CRC risk is largely unknown. We performed a genome-wide investigation of CNVs on genomic DNA from 384 familial CRC cases and 1,285 healthy controls by the Affymetrix 6.0 array. An increase of overall CNV burden was observed in familial CRC patients compared to healthy controls, especially for CNVs larger than 50 kb (case/control ratio = 1.66, P = 0.025). In addition, we discovered for the first time a novel structural variation at 12p12.3 and determined the breakpoints by strategic PCR and sequencing. This 12p12.3 structural variation was found in four of 2,862 CRC cases, but not in 6,243 healthy controls (P = 0.0098). RERGL gene (RERG/RAS-like), the only gene influenced by the 12p12.3 structural variation, sharing most of the conserved regions with its close family member RERG tumor suppressor gene (RAS-like, estrogen-regulated, growth inhibitor), might be a novel CRC related gene. In conclusion, this is the first study to reveal the contribution of the overall burden of CNVs to familial CRC risk, and identified a novel rare structural variation at 12p12.3 containing RERGL gene to be associated with CRC.
    Carcinogenesis 10/2013; · 5.64 Impact Factor
  • Michael Krawczak, Jürgen Goebel
    Deutsche Zeitschrift für die Gesamte Gerichtliche Medizin 09/2013; · 2.69 Impact Factor
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    ABSTRACT: Human longevity is a multifactorial phenotype influenced by both genetic and environmental factors. Despite its heritability of 25-32 %, the genetic background of longevity is as yet largely unexplained. Apart from APOE status, variation in the FOXO3A gene is the only confirmed genetic contributor to survival into old age. On the other hand, FOXO3A activity is known to be downregulated in various cancers, and the gene was recently identified as a novel deletion hotspot in human lung adenocarcinoma. In view of the strong association between smoking and lung cancer, we set out to explore whether smoking modifies the known association between FOXO3A variation and longevity. To this end, we conducted a case-control study in two different populations, drawing upon extensive collections of old-aged individuals and younger controls available to us (1,613 German centenarians/nonagenarians and 1,104 controls; 1,088 Danish nonagenarians and 736 controls). In the German sample, 21 single nucleotide polymorphisms (SNPs) from the FOXO3A gene region were genotyped, whereas 15 FOXO3A SNPs were analyzed in the Danish sample. Eight SNPs were typed in both populations. Logistic regression analysis revealed that adjustment for smoking does not systematically alter the association between FOXO3A variation and longevity in neither population. Our analysis therefore suggests that the said association is not largely due to the confounding effects of lung cancer.
    Age 09/2013; · 6.28 Impact Factor
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    ABSTRACT: Jörg Jenatsch was a Swiss defender of independence and a fighter for liberty in the 17th century. With the help of three living male members of the Jenatsch family, we successfully identified a skeleton exhumed from Chur cathedral as the remains of Jörg Jenatsch. Our conclusion was based upon complete Y-STR and Y-SNP profiles that could be generated by replicate analyses of a bone sample available to us. The skeleton and the three living family members carried the same Y-SNP haplogroup, but were discordant at three of 23 Y-STR loci. This notwithstanding, conservative biostatistical evaluation of the data suggests that the Chur skeleton is at least 20 times more likely than not to be Jörg Jenatsch.
    Forensic Science International: Genetics 08/2013; · 3.86 Impact Factor
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    ABSTRACT: Abstract Background: Higher fetuin-A levels have been linked to fatty liver disease (FLD), the most common cause of elevated alanine aminotransferase (ALT) levels, but associations between ALT and fetuin-A level have been inconsistent. The presence of the metabolic syndrome in individuals with elevated ALT levels has been shown to characterize more severe FLD. Thus, aim of the study was to investigate the association between fetuin-A level and the coexistence of elevated ALT levels and metabolic syndrome (ALT-MetS). Methods: A population-based cross-sectional study including 728 individuals (age 50-77 years) was conducted. We used multivariable logistic regression analysis to assess the association between serum fetuin-A level and the dichotomous outcome ALT-MetS, defined as coexistence of elevated ALT level (>75th percentile) and metabolic syndrome (any three of the components: abdominal obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, abnormal glucose metabolism). Results: Individuals with a high fetuin-A level had an odds ratio (OR) for ALT-MetS of 2.22 [95% confidence interval (CI) 1.36-3.63; Ptrend=<0.001] comparing extreme tertiles. After excluding individuals with cancer, stroke, or myocardial infarction, individuals with high fetuin-A levels had an OR for ALT-MetS of 2.48 (95% CI 1.38-4.47) comparing extreme tertiles, and we observed statistical interaction between fetuin-A level and age (P=0.048). Fetuin-A level was associated with ALT-MetS in young individuals, defined as <64 years of age (OR 3.30, 95% CI 1.45-7.55; Ptrend=0.004), and not statistically significant in older individuals (OR 1.79, 95% CI 0.74-4.31; Ptrend=0.197). Conclusions: Fetuin-A level was positively associated with ALT-MetS, particularly in younger individuals. Prospective studies in larger populations are warranted.
    Metabolic syndrome and related disorders 08/2013;
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries. Liver samples from morbidly obese patients (n = 45) with all stages of NAFLD and controls (n = 18) were analyzed by array-based DNA methylation and mRNA expression profiling. NAFLD-specific expression and methylation differences were seen for nine genes coding for key enzymes in intermediate metabolism (including PC, ACLY, and PLCG1) and insulin/insulin-like signaling (including IGF1, IGFBP2, and PRKCE) and replicated by bisulfite pyrosequening (independent n = 39). Transcription factor binding sites at NAFLD-specific CpG sites were >1,000-fold enriched for ZNF274, PGC1A, and SREBP2. Intraindividual comparison of liver biopsies before and after bariatric surgery showed NAFLD-associated methylation changes to be partially reversible. Postbariatric and NAFLD-specific methylation signatures were clearly distinct both in gene ontology and transcription factor binding site analyses, with >400-fold enrichment of NRF1, HSF1, and ESRRA sites. Our findings provide an example of treatment-induced epigenetic organ remodeling in humans.
    Cell metabolism 08/2013; 18(2):296-302. · 17.35 Impact Factor
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    ABSTRACT: Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM. Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10(-9)) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.
    European Heart Journal 07/2013; · 14.72 Impact Factor
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    ABSTRACT: Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as 'reduced (or incomplete) penetrance'. Reduced penetrance is not uncommon; indeed, there are many known examples of 'disease-causing mutations' that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.
    Human Genetics 07/2013; · 4.63 Impact Factor
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    ABSTRACT: Die Entwicklung der DNA-Sequenzierungstechnologien stellt die humane Genomforschung vor große datenschutzrechtliche und ethische Herausforderungen. Der heute bereits mögliche tiefe Einblick in die genetische Ausstattung eines Menschen kann von enormer Bedeutung für dessen aktuelles und zukünftiges gesundheitliches Befinden sein. Genomische Daten lassen zudem Rückschlüsse auf die Identität und die genetischen Eigenschaften enger Blutsverwandter zu. Wegen ihres inhärenten Personenbezugs bedürfen genomische Daten somit eines besonders sorgfältigen Umgangs. Zentrale Elemente eines verantwortungsvollen Managements von Genomdaten im Rahmen von Forschungsprojekten sind neben der angemessenen Einwilligung der Teilnehmer auch die Anonymisierung/Pseudonymisierung der Daten und die Trennung der Datenhoheit. Außerdem müssen im Sinne der guten wissenschaftlichen Praxis Fristen und Verordnungen für die Aufbewahrung der Daten beachtet werden. Diese Aspekte werden im vorliegenden Artikel dargestellt und hinsichtlich ihrer praktischen Umsetzung diskutiert.
    Medizinische Genetik 06/2013; 25(2). · 0.09 Impact Factor
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    ABSTRACT: BACKGROUND& AIMS: Genome-wide association studies (GWASs) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies. METHODS: We sequenced whole exomes of 42 unrelated subjects with Crohn's disease (CD) and 5 healthy individuals (controls), and then filtered single-nucleotide variants by incorporating association results from meta-analyses of CD GWASs and in silico mutation effect prediction algorithms. We then genotyped 9348 patients with CD, 2868 with ulcerative colitis, and 14,567 controls, and associated variants analyzed in functional studies using materials from patients and controls and in vitro model systems. RESULTS: We identified rare missense mutations in PR domain-containing1 (PRDM1) and associated these with CD. These increased proliferation of T cells and secretion of cytokines upon activation, and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWASs, correlated with reduced expression of PRDM1 in ileal biopsies and peripheral blood mononuclear cells (combined P=1.6×0(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P=4.83×10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit NFκB activation of genes that regulate inflammation and affect stability of proteins in toll-like receptor pathways. CONCLUSIONS: We have extended GWAS results and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWASs and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role for autophagy in pathogenesis of CD.
    Gastroenterology 04/2013; · 12.82 Impact Factor
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    ABSTRACT: Numerous studies of human populations in Europe and Asia have revealed a concordance between their extant genetic structure and the prevailing regional pattern of geography and language. For native South Americans, however, such evidence has been lacking so far. Therefore, we examined the relationship between Y-chromosomal genotype on the one hand, and male geographic origin and linguistic affiliation on the other, in the largest study of South American natives to date in terms of sampled individuals and populations. A total of 1,011 individuals, representing 50 tribal populations from 81 settlements, were genotyped for up to 17 short tandem repeat (STR) markers and 16 single nucleotide polymorphisms (Y-SNPs), the latter resolving phylogenetic lineages Q and C. Virtually no structure became apparent for the extant Y-chromosomal genetic variation of South American males that could sensibly be related to their inter-tribal geographic and linguistic relationships. This continent-wide decoupling is consistent with a rapid peopling of the continent followed by long periods of isolation in small groups. Furthermore, for the first time, we identified a distinct geographical cluster of Y-SNP lineages C-M217 (C3*) in South America. Such haplotypes are virtually absent from North and Central America, but occur at high frequency in Asia. Together with the locally confined Y-STR autocorrelation observed in our study as a whole, the available data therefore suggest a late introduction of C3* into South America no more than 6,000 years ago, perhaps via coastal or trans-Pacific routes. Extensive simulations revealed that the observed lack of haplogroup C3* among extant North and Central American natives is only compatible with low levels of migration between the ancestor populations of C3* carriers and non-carriers. In summary, our data highlight the fact that a pronounced correlation between genetic and geographic/cultural structure can only be expected under very specific conditions, most of which are likely not to have been met by the ancestors of native South Americans.
    PLoS Genetics 04/2013; 9(4):e1003460. · 8.52 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies. METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems. RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways. CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
    Gastroenterology 01/2013; 145(2):339-47. · 12.82 Impact Factor
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    ABSTRACT: Angesichts der zunehmenden Datenflut in der Genomforschung wird ein effizientes Forschungsdatenmanagement, verbunden mit einer sicheren und nachhaltigen Archivierung, auch in diesem Wissenschaftsbereich immer wichtiger. Der letzte von 3 Artikeln der Reihe ,,Forschungsdatenmanagement von Genomdaten“ beschreibt allgemein den Lebenszyklus von Forschungsdaten – ausgehend von deren Planung, über die Auswahl und Übernahme der Daten für die Speicherung bis hin zu notwendigen Erhaltungsmaßnahmen und dem Zugriff durch Datennutzer. Archive spielen in fast allen Phasen dieses Zyklus eine Rolle und bilden daher eine wichtige Komponente der Verarbeitung von Genomdaten. Beispielhaft werden 3 öffentliche europäische Archive für Genomdaten vorgestellt: die Datenbank des European Molecular Biology Laboratory (EMBL), das Sequence Read Archive und das Trace Archive. Da jede dieser Einrichtungen jedoch auf eine bestimmte Art von Daten spezialisiert ist, bleibt ein Bedarf an zusätzlichen Langzeitarchiven, die flexibel mit verschiedenen Datentypen umgehen bzw. auf zusätzliche Datentypen erweitert werden können. Für solche Archive wird ein generisches Konzept beschrieben und mit Empfehlungen für dessen praktische Umsetzung verbunden.
    Medizinische Genetik 01/2013; 25(3). · 0.09 Impact Factor
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    ABSTRACT: To date, liver biopsy is the only means of reliable diagnosis for fatty liver disease (FLD). Owing to the inevitable biopsy-associated health risks, however, the development of valid noninvasive diagnostic tools for FLD is well warranted. We evaluated a particular metabolic profile with regard to its ability to diagnose FLD and compared its performance to that of established phenotypes, conventional biomarkers and disease-associated genotypes. The study population comprised 115 patients with ultrasound-diagnosed FLD and 115 sex- and age-matched controls for whom the serum concentration was measured of 138 different metabolites, including acylcarnitines, amino acids, biogenic amines, hexose, phosphatidylcholines (PCs), lyso-PCs and sphingomyelins. Established phenotypes, biomarkers, disease-associated genotypes and metabolite data were included in diagnostic models for FLD using logistic regression and partial least-squares discriminant analysis. The discriminative power of the ensuing models was compared with respect to area under curve (AUC), integrated discrimination improvement (IDI) and by way of cross-validation (CV). Use of metabolic markers for predicting FLD showed the best performance among all considered types of markers, yielding an AUC of 0.8993. Additional information on phenotypes, conventional biomarkers or genotypes did not significantly improve this performance. Phospholipids and branched-chain amino acids were most informative for predicting FLD. We show that the inclusion of metabolite data may substantially increase the power to diagnose FLD over that of models based solely upon phenotypes and conventional biomarkers.
    PLoS ONE 01/2013; 8(10):e76813. · 3.53 Impact Factor

Publication Stats

15k Citations
2,171.48 Total Impact Points

Institutions

  • 2013
    • University of Zurich
      • Centre for Evolutionary Medicine - EZM
      Zürich, Zurich, Switzerland
  • 2003–2013
    • Christian-Albrechts-Universität zu Kiel
      • • Institute of Clinical Molecular Biology
      • • UKSH Institut für Medizinische Informatik und Statistik
      Kiel, Schleswig-Holstein, Germany
  • 1998–2013
    • Charité Universitätsmedizin Berlin
      • • Institute of Legal Medicine and Forensic Sciences
      • • Institute of Medical Genetics and Human Genetics
      Berlin, Land Berlin, Germany
  • 2012
    • Aalborg University
      • Department of Mathematical Sciences
      Aalborg, Region North Jutland, Denmark
  • 2004–2012
    • Universitätsklinikum Schleswig - Holstein
      • Institut für Medizinische Informatik und Statistik (Kiel)
      Kiel, Schleswig-Holstein, Germany
  • 2011
    • Universität Bern
      • Department of Clinical Pharmacology and Visceral Research
      Bern, BE, Switzerland
  • 2005–2011
    • University Medical Center Schleswig-Holstein
      Kiel, Schleswig-Holstein, Germany
  • 2010
    • Beijing Genomics Institute
      Bao'an, Guangdong, China
  • 2008–2009
    • Leibniz Institute for Age Research - Fritz Lipmann Institute
      • Genome Analysis
      Jena, Thuringia, Germany
  • 1992–2009
    • Hannover Medical School
      • Institute for Human Genetics
      Hannover, Lower Saxony, Germany
  • 2001–2008
    • German Primate Center
      Göttingen, Lower Saxony, Germany
    • University of Geneva
      Genève, Geneva, Switzerland
  • 1996–2008
    • Cardiff University
      • • School of Medicine
      • • Institute of Medical Genetics
      • • School of Computer Science and Informatics
      Cardiff, WLS, United Kingdom
    • Maine Institute for Human Genetics and Health
      Bangor, Maine, United States
  • 1990–2008
    • Charles University in Prague
      • • Department of Biology and Medical Genetics (2. LF)
      • • Ústav klinické biochemie a patobiochemie (2. LF)
      Praha, Praha, Czech Republic
    • University College London
      Londinium, England, United Kingdom
  • 2007
    • Leuphana University Lüneburg
      Luneberg, Lower Saxony, Germany
    • Erasmus MC
      • Department of Forensic Molecular Biology
      Rotterdam, South Holland, Netherlands
  • 2006
    • Universität Heidelberg
      • Institute of Human Genetics
      Heidelberg, Baden-Wuerttemberg, Germany
    • Duke University
      • Department of Biology
      Durham, NC, United States
  • 1993–2005
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 1996–2004
    • University of Wales
      • Department of Computer Science
      Cardiff, Wales, United Kingdom
  • 2002–2003
    • San Diego Zoo
      San Diego, California, United States
  • 2001–2003
    • University of Leipzig
      • Institut für Rechtsmedizin
      Leipzig, Saxony, Germany
  • 1990–1999
    • Thrombosis Research Institute
      Londinium, England, United Kingdom
  • 1991
    • MRC Clinical Sciences Centre
      London Borough of Harrow, England, United Kingdom
  • 1985–1991
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany
  • 1988–1990
    • Universitätsmedizin Göttingen
      • Department of Human Genetics
      Göttingen, Lower Saxony, Germany
  • 1989
    • University of London
      Londinium, England, United Kingdom