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CONAN: copy number variation analysis software for genome-wide association studies
Lukas Forer, Sebastian Sch?nherr, Hansi Weissensteiner, Florian Haider, Thomas Kluckner, Christian Gieger, Heinz-Erich Wichmann, Günther Specht, Florian Kronenberg, Anita Kloss-Brandst?tter
BMC Bioinformatics , 2010, DOI: 10.1186/1471-2105-11-318
Abstract: CONAN is a freely available client-server software solution which provides an intuitive graphical user interface for categorizing, analyzing and associating CNVs with phenotypes. Moreover, CONAN assists the evaluation process by visualizing detected associations via Manhattan plots in order to enable a rapid identification of genome-wide significant CNV regions. Various file formats including the information on CNVs in population samples are supported as input data.CONAN facilitates the performance of GWAS based on CNVs and the visual analysis of calculated results. CONAN provides a rapid, valid and straightforward software solution to identify genetic variation underlying the 'missing' heritability for complex traits that remains unexplained by recent GWAS. The freely available software can be downloaded at http://genepi-conan.i-med.ac.at webcite.Genome-wide association studies (GWAS) have identified associations between various phenotypes and common sequence polymorphisms, which might play a role for disease development (for a comprehensive overview see [1]). For most common diseases, these discoveries collectively explain only a modest fraction (1-15%) of heritable variation of the phenotype [2]. Recently, genome re-sequencing studies demonstrated that most bases that vary among human genomes reside in copy number variations (CNVs) [3]. CNVs are genomic segments which are duplicated or deleted among different individuals, ranging from kilobases to several megabases in length [4]. Although at least 20% of the genome was found to be copy number variable, this class of variation is, nonetheless, poorly integrated into human genetic studies. However, part of the heritability void left by GWAS could be accounted for common CNVs. Indeed, several CNVs were recently described to be associated with complex traits: a 20-kb deletion upstream of the IRGM gene with Crohn's disease [5], a 45-kb deletion upstream of NEGR1 with body mass index [6], a 32-kb deletion with psoriasi
Gene Set of Nuclear-Encoded Mitochondrial Regulators Is Enriched for Common Inherited Variation in Obesity
Nadja Knoll, Ivonne Jarick, Anna-Lena Volckmar, Martin Klingenspor, Thomas Illig, Harald Grallert, Christian Gieger, Heinz-Erich Wichmann, Annette Peters, Johannes Hebebrand, André Scherag, Anke Hinney
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055884
Abstract: There are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1) 16 nuclear regulators of mitochondrial genes, (2) 91 genes for oxidative phosphorylation and (3) 966 nuclear-encoded mitochondrial genes). Gene set enrichment analysis (GSEA) showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS) data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios (extremely obese child and both biological parents) and a population-based GWAS sample (KORA F4, n = 1,743). A meta-analysis was performed on all three samples. In each sample, the distribution of significance levels between the respective gene set and those of all genes was compared using the leading-edge-fraction-comparison test (cut-offs between the 50th and 95th percentile of the set of all gene-wise corrected p-values) as implemented in the MAGENTA software. In the case-control sample, significant enrichment of associations with obesity was observed above the 50th percentile for the set of the 16 nuclear regulators of mitochondrial genes (pGSEA,50 = 0.0103). This finding was not confirmed in the trios (pGSEA,50 = 0.5991), but in KORA (pGSEA,50 = 0.0398). The meta-analysis again indicated a trend for enrichment (pMAGENTA,50 = 0.1052, pMAGENTA,75 = 0.0251). The GSEA revealed that weak association signals for obesity might be enriched in the gene set of 16 nuclear regulators of mitochondrial genes.
Population-genetic comparison of the Sorbian isolate population in Germany with the German KORA population using genome-wide SNP arrays
Arnd Gross, Anke T?njes, Peter Kovacs, Krishna R Veeramah, Peter Ahnert, Nab R Roshyara, Christian Gieger, Ina-Maria Rueckert, Markus Loeffler, Mark Stoneking, Heinz-Erich Wichmann, John Novembre, Michael Stumvoll, Markus Scholz
BMC Genetics , 2011, DOI: 10.1186/1471-2156-12-67
Abstract: The degree of relatedness was significantly higher in the Sorbs. Principal components analysis revealed a west to east clustering of KORA individuals born in Germany, KORA individuals born in Poland or Czech Republic, Half-Sorbs (less than four Sorbian grandparents) and Full-Sorbs. The Sorbs cluster is nearest to the cluster of KORA individuals born in Poland. The number of rare SNPs is significantly higher in the Sorbs sample. FST between KORA and Sorbs is an order of magnitude higher than between different regions in Germany. Compared to the other populations, Sorbs show a higher proportion of individuals with runs of homozygosity between 2.5 Mb and 5 Mb. Linkage disequilibrium (LD) at longer range is also slightly increased but this has no effect on the power of association studies.Oversampling of families in the Sorbs sample causes detectable bias regarding higher FST values and higher LD but the effect is an order of magnitude smaller than the observed differences between KORA and Sorbs. Relatedness in the Sorbs also influenced the power of uncorrected association analyses.Sorbs show signs of genetic isolation which cannot be explained by over-sampling of relatives, but the effects are moderate in size. The Slavonic origin of the Sorbs is still genetically detectable.Regarding LD structure, a clear advantage for genome-wide association studies cannot be deduced. The significant amount of cryptic relatedness in the Sorbs sample results in inflated variances of Beta-estimators which should be considered in genetic association analyses.The Sorbs living in the Upper Lusatia region of Eastern Saxony are one of the few historic ethnic minorities in Germany. They are of Slavonic origin speaking a west Slavic language (Sorbian), and it is assumed that they have lived in ethnic isolation among the German majority during the past 1100 years [1]. Therefore, this population may be of special interest for genetic studies of complex traits.The value of isolated populations f
Early onset lung cancer, cigarette smoking and the SNP309 of the murine double minute-2 (MDM2) gene
Kirstin Mittelstrass, Wiebke Sauter, Albert Rosenberger, Thomas Illig, Maria Timofeeva, Norman Klopp, Hendrik Dienemann, Eckart Meese, Gerhard Sybrecht, Gabi Woelke, Mathias Cebulla, Maria Degen, Harald Morr, Peter Drings, Andreas Groeschel, Karsten Kreymborg, Karl Haeu?inger, Gerd Hoeffken, Christine Schmidt, Bettina Jilge, Wilhelm Schmidt, You-Dschun Ko, Dagmar Taeuscher, Jenny Chang-Claude, Heinz-Erich Wichmann, Heike Bickeboeller, Angela Risch
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-113
Abstract: We used 635 Caucasian patients diagnosed with lung cancer before 51 years of age and 1300 healthy gender and age frequency matched population Caucasian controls to investigate the association between the MDM2 SNP309 and the risk of developing early onset lung cancer. Conditional logistic models were applied to assess the genotype-phenotype association, adjusted for smoking.Compared to the GG genotype, the adjusted ORs for the TG and TT genotype were 0.9 (95% CI: 0.7–1.5) and 1.0 (95% CI: 0.7–1.5), respectively. Also no association was found for histological subtypes of lung cancer. The strength of this study is that within young cases the genetic component to develop lung cancer may be greater. Our results indicate that the MDM2 SNP309 is not significantly associated with lung carcinogenesis but point towards gender-specific differences.Human cells have developed a complex system to protect themselves from genotoxic damage where the p53 tumor suppressor gene plays an important role in protecting against such insults by serving as an integrator of the signals produced by DNA damage. The MDM2 protein inhibits p53 transactivation activity and promotes its export from the nucleus by binding to the transcriptional activation domain of p53 [1] and acts as an ubiquitin ligase upon p53 pushing fast degradation of the suppressor [2,3].Recently, a SNP (SNP309, G2580T) at the intronic p53-response promoter of MDM2 was identified and associated with altered Sp1 binding affinity and expression levels of MDM2 RNA and protein [4]. Contradictory results were reported regarding the MDM2 SNP309 association with lung cancer [5-8]. In addition the polymorphism was correlated with a decreased age at the time of lung cancer diagnosis in Li-Fraumeni syndrome and sporadic sarcoma patients [4]. Our study is the first report on a large German case-control study of young lung cancer patients (age of onset < 51 years) investigating the MDM2 SNP 309.The study population consists of 635 lung can
Mitochondrial DNA Variants in Obesity
Nadja Knoll, Ivonne Jarick, Anna-Lena Volckmar, Martin Klingenspor, Thomas Illig, Harald Grallert, Christian Gieger, Heinz-Erich Wichmann, Annette Peters, Susanna Wiegand, Heike Biebermann, Pamela Fischer-Posovszky, Martin Wabitsch, Henry V?lzke, Matthias Nauck, Alexander Teumer, Dieter Rosskopf, Christian Rimmbach, Stefan Schreiber, Gunnar Jacobs, Wolfgang Lieb, Andre Franke, Johannes Hebebrand, Anke Hinney
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094882
Abstract: Heritability estimates for body mass index (BMI) variation are high. For mothers and their offspring higher BMI correlations have been described than for fathers. Variation(s) in the exclusively maternally inherited mitochondrial DNA (mtDNA) might contribute to this parental effect. Thirty-two to 40 mtDNA single nucleotide polymorphisms (SNPs) were available from genome-wide association study SNP arrays (Affymetrix 6.0). For discovery, we analyzed association in a case-control (CC) sample of 1,158 extremely obese children and adolescents and 435 lean adult controls. For independent confirmation, 7,014 population-based adults were analyzed as CC sample of n = 1,697 obese cases (BMI≥30 kg/m2) and n = 2,373 normal weight and lean controls (BMI<25 kg/m2). SNPs were analyzed as single SNPs and haplogroups determined by HaploGrep. Fisher's two-sided exact test was used for association testing. Moreover, the D-loop was re-sequenced (Sanger) in 192 extremely obese children and adolescents and 192 lean adult controls. Association testing of detected variants was performed using Fisher's two-sided exact test. For discovery, nominal association with obesity was found for the frequent allele G of m.8994G/A (rs28358887, p = 0.002) located in ATP6. Haplogroup W was nominally overrepresented in the controls (p = 0.039). These findings could not be confirmed independently. For two of the 252 identified D-loop variants nominal association was detected (m.16292C/T, p = 0.007, m.16189T/C, p = 0.048). Only eight controls carried the m.16292T allele, five of whom belonged to haplogroup W that was initially enriched among these controls. m.16189T/C might create an uninterrupted poly-C tract located near a regulatory element involved in replication of mtDNA. Though follow-up of some D-loop variants still is conceivable, our hypothesis of a contribution of variation in the exclusively maternally inherited mtDNA to the observed larger correlations for BMI between mothers and their offspring could not be substantiated by the findings of the present study.
Association of daily tar and nicotine intake with incident myocardial infarction: Results from the population-based MONICA/KORA Augsburg Cohort Study 1984 - 2002
Qiu-Li Zhang, Jens Baumert, Karl-Heinz Ladwig, H-Erich Wichmann, Christa Meisinger, Angela D?ring
BMC Public Health , 2011, DOI: 10.1186/1471-2458-11-273
Abstract: The study was based on 4,099 men and 4,197 women participating in two population-based MONICA Augsburg surveys between 1984 and 1990 and followed up within the KORA framework until 2002. During a mean follow-up of 13.3 years, a number of 307 men and 80 women developed an incident MI event. Relative risks were calculated as hazard ratios (HRs) estimated by Cox proportional hazards models adjusted for cardiovascular risk factors.In the present study, male regular smokers consumed on average more cigarettes per day than female regular smokers (20 versus 15) and had a higher tar and nicotine intake per day. In men, the MI risk compared to never-smokers increased with higher tar intake: HRs were 2.24 (95% CI 1.40-3.56) for 1-129 mg/day, 2.12 (95% CI 1.37-3.29) for 130-259 mg/day and 3.01 (95% CI 2.08-4.36) for ≥ 260 mg/day. In women, the corresponding associations were comparable but more pronounced for high tar intake (HR 4.67, 95% CI 1.76-12.40). Similar associations were observed for nicotine intake.The present study based on a large population-based sample adds important evidence of cumulative effects of tar and nicotine intake on the risk of incident MI. Even low or medium tar and nicotine intake revealed substantial risk increases as compared to never-smokers. Therefore, reduction of tar and nicotine contents in cigarettes cannot be seen as a suitable public health policy in preventing myocardial infarction.Cigarette smoking is a central issue in public health policy as it has been shown to be associated with an elevated risk of various cardiovascular diseases and types of cancer [1,2]. Smoking has been determined as one of the most important risk factors for myocardial infarction (MI) [3-5], but it was shown that smoking cessation can reduce this risk [6]. Many countries and international agencies have made great efforts to change smoking behaviour and to encourage smokers to quit smoking, e.g. by preventing initiation of tobacco use, promoting cessation among ado
Extensive Natural Variation for Cellular Hydrogen Peroxide Release Is Genetically Controlled
Homa Attar, Karen Bedard, Eugenia Migliavacca, Maryline Gagnebin, Yann Dupré, Patrick Descombes, Christelle Borel, Samuel Deutsch, Holger Prokisch, Thomas Meitinger, Divya Mehta, Erich Wichmann, Jean Maurice Delabar, Emmanouil T. Dermitzakis, Karl-Heinz Krause, Stylianos E. Antonarakis
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043566
Abstract: Natural variation in DNA sequence contributes to individual differences in quantitative traits. While multiple studies have shown genetic control over gene expression variation, few additional cellular traits have been investigated. Here, we investigated the natural variation of NADPH oxidase-dependent hydrogen peroxide (H2O2 release), which is the joint effect of reactive oxygen species (ROS) production, superoxide metabolism and degradation, and is related to a number of human disorders. We assessed the normal variation of H2O2 release in lymphoblastoid cell lines (LCL) in a family-based 3-generation cohort (CEPH-HapMap), and in 3 population-based cohorts (KORA, GenCord, HapMap). Substantial individual variation was observed, 45% of which were associated with heritability in the CEPH-HapMap cohort. We identified 2 genome-wide significant loci of Hsa12 and Hsa15 in genome-wide linkage analysis. Next, we performed genome-wide association study (GWAS) for the combined KORA-GenCord cohorts (n = 279) using enhanced marker resolution by imputation (>1.4 million SNPs). We found 5 significant associations (p<5.00×10?8) and 54 suggestive associations (p<1.00×10?5), one of which confirmed the linked region on Hsa15. To replicate our findings, we performed GWAS using 58 HapMap individuals and ~2.1 million SNPs. We identified 40 genome-wide significant and 302 suggestive SNPs, and confirmed genome signals on Hsa1, Hsa12, and Hsa15. Genetic loci within 900 kb from the known candidate gene p67phox on Hsa1 were identified in GWAS in both cohorts. We did not find replication of SNPs across all cohorts, but replication within the same genomic region. Finally, a highly significant decrease in H2O2 release was observed in Down Syndrome (DS) individuals (p<2.88×10?12). Taken together, our results show strong evidence of genetic control of H2O2 in LCL of healthy and DS cohorts and suggest that cellular phenotypes, which themselves are also complex, may be used as proxies for dissection of complex disorders.
Posttraumatic Stress Disorder and Not Depression Is Associated with Shorter Leukocyte Telomere Length: Findings from 3,000 Participants in the Population-Based KORA F4 Study
Karl-Heinz Ladwig, Anne Catharina Brockhaus, Jens Baumert, Karoline Lukaschek, Rebecca T. Emeny, Johannes Kruse, Veryan Codd, Sibylle H?fner, Eva Albrecht, Thomas Illig, Nilesh J. Samani, H. Erich Wichmann, Christian Gieger, Annette Peters
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064762
Abstract: Background A link between severe mental stress and shorter telomere length (TL) has been suggested. We analysed the impact of Posttraumatic Stress Disorder (PTSD) on TL in the general population and postulated a dose-dependent TL association in subjects suffering from partial PTSD compared to full PTSD. Methods Data are derived from the population-based KORA F4 study (2006–2008), located in southern Germany including 3,000 individuals (1,449 men and 1,551 women) with valid and complete TL data. Leukocyte TL was measured using a quantitative PCR-based technique. PTSD was assessed in a structured interview and by applying the Posttraumatic Diagnostic Scale (PDS) and the Impact of Event Scale (IES). A total of 262 (8.7%) subjects qualified for having partial PTSD and 51 (1.7%) for full PTSD. To assess the association of PTSD with the average TL, linear regression analyses with adjustments for potential confounding factors were performed. Results The multiple model revealed a significant association between partial PTSD and TL (beta = ?0.051, p = 0.009) as well as between full PTSD and shorter TL (beta = ?0.103, p = 0.014) indicating shorter TL on average for partial and full PTSD. An additional adjustment for depression and depressed mood/exhaustion gave comparable beta estimations. Conclusions Participants with partial and full PTSD had significantly shorter leukocyte TL than participants without PTSD. The dose-dependent variation in TL of subjects with partial and full PTSD exceeded the chronological age effect, and was equivalent to an estimated 5 years in partial and 10 years in full PTSD of premature aging.
GMS Medizinische Informatik, Biometrie und Epidemiologie - das neue e-Journal der GMDS
Wichmann, H.-Erich,K?pcke, Wolfgang
GMS Medizinische Informatik, Biometrie und Epidemiologie , 2005,
Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers
Kirstin Mittelstrass equal contributor,Janina S. Ried equal contributor,Zhonghao Yu equal contributor,Jan Krumsiek,Christian Gieger,Cornelia Prehn,Werner Roemisch-Margl,Alexey Polonikov,Annette Peters,Fabian J. Theis,Thomas Meitinger,Florian Kronenberg,Stephan Weidinger,Heinz Erich Wichmann,Karsten Suhre,Rui Wang-Sattler,Jerzy Adamski ? ,Thomas Illig ?
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002215
Abstract: Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8×10?4; Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8×10?10; Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation.
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