1,340 research outputs found
Genetic Variants in WNT16 and PKD2L1 Locus Affect Heel Ultrasound Bone Stiffness: Analyses from the General Population and Patients Evaluated for Osteoporosis
No full textOsteoporosis, a complex chronic disease with increasing prevalence, is characterised by reduced bone mineral density (BMD) and increased fracture risk. The high heritability of BMD suggests substantial impact of the individual genetic disposition on bone phenotypes and the development of osteoporosis. In the past years, genome-wide association studies (GWAS) identified hundreds of genetic variants associated with BMD or osteoporosis. Here, we analysed 1103 single nucleotide polymorphisms (SNPs), previously identified as associated with estimated BMD (eBMD) in the UK Biobank. We assessed whether these SNPs are related to heel stiffness index obtained by quantitative ultrasound in 5665 adult participants of the Study of Health in Pomerania (SHIP). We confirmed 45 significant associations after correction for multiple testing. Next, we analysed six selected SNPs in 631 patients evaluated for osteoporosis [rs2707518 (CPED1/WNT16), rs3779381 (WNT16), rs115242848 (LOC101927709/EN1), rs10239787 (JAZF1), rs603424 (PKD2L1) and rs6968704 (JAZF1)]. Differences in minor allele frequencies (MAF) of rs2707518 and rs3779381 between SHIP participants (higher MAF) and patients evaluated for osteoporosis (lower MAF) indicated a protective effect of the minor allele on bone integrity. In contrast, differences in MAF of rs603424 indicated a harmful effect. Co-localisation analyses indicated that the rs603424 effect may be mediated via stearoyl-CoA desaturase (SCD) expression, an enzyme highly expressed in adipose tissue with a crucial role in lipogenesis. Taken together, our results support the role of the WNT16 pathway in the regulation of bone properties and indicate a novel causal role of SCD expression in adipose tissue on bone integrity
Common Methods for Performing Mendelian Randomization
No full textMendelian randomization (MR) is a framework for assessing causal inference using cross-sectional data in combination with genetic information. This paper summarizes statistical methods commonly applied and strait forward to use for conducting MR analyses including those taking advantage of the rich dataset of SNP-trait associations that were revealed in the last decade through large-scale genome-wide association studies. Using these data, powerful MR studies are possible. However, the causal estimate may be biased in case the assumptions of MR are violated. The source and the type of this bias are described while providing a summary of the mathematical formulas that should help estimating the magnitude and direction of the potential bias depending on the specific research setting. Finally, methods for relaxing the assumptions and for conducting sensitivity analyses are discussed. Future researches in the field of MR include the assessment of non-linear causal effects, and automatic detection of invalid instruments
Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function
No full textADHA a ADD v rodině v kontextu osobní historie
No full textThis thesis deals with ADHD / ADD syndrome. My work will try to outline and clarify this issue from the perspective of personal history. In the theoretical part, the aim was to focus on available knowledge about ADHD and ADD. The terms family and family with a child with ADHD / ADD have been defined. In the practical part, the aim was to describe the situation of ADHD and ADHD syndrome in my family, to summarize the experience and to outline how ADHD and ADD manifest in real life by providing case studies
White Blood Cells and Blood Pressure: A Mendelian Randomization Study
No full textBackground: High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension. Methods: We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and used Mendelian randomization (MR) analyses using the ≈750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP. Results: A positive association between quintiles of lymphocyte, monocyte, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm Hg for neutrophil counts; all P<10-50). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19-1.20] and 0.56 [95% CI, 0.23-0.90] of mm Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. The exclusion of rs3184504 SNP in the SH2B3 locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils, and eosinophils but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio. Conclusions: Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP
Development of a hole system for introducing holes in a car Front
No full textDurch Schweißverzug bei der Fertigung von PKW- Vorderachsen ist eine Folgebearbeitung für die Einbringung von tolerierten Aufnahmelöchern durch eine wirtschaftlich arbeitende Gesamtlochanlage, welche alle Randbedingungen erfüllt, unabdingbar. Die Diplomarbeit befasst sich mit der Entwicklung und Optimierung der Lochanlage 4, einer Locheinheit in der Gesamtlochanlage, welche aus mehreren Locheinheiten und einem Transfersystem besteht. Das Stanzen als Lochungsmethode und die zur Übersichtlichkeit beim Konstruieren der Lochanlage in Teilfunktionsvarianten untersuchten Konstruktionslösungen wurden mittel Nutzwertanalysen bewertet. Durch die in horizontaler Richtung bewegliche Matrizenaufnahme, die zwischen zwei ebenfalls in dieser Richtung beweglichen Stempeln sitzt und als oberes Teilsystem insgesamt auch in vertikale Richtung in die zweischalige PKW- Vorderachse hinein- und herausfahrbar ist, wurde die Einbringung der beiden Löcher in das geometrisch komplexe Werkstück gelöst. Die Konstruktion der Lochanlage mittels CAD- Software ist mit allen zugehörigen Konstruktionszeichnungen, Stücklisten und zugehörigen Unterlagen für die Fertigung und Montage dokumentiert. Hoch belastete Konstruktionsteile werden in Varianten mit der FEM optimiert und ausgewertet. Über Simulationssoftware werden Automatisierbarkeit und Taktzeit des Anlagenablaufs nachgewiesen
Modulation of genetic associations with serum urate levels by body-mass-index in humans
No full textWe tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.</p
Microarray-based Genome-Wide Association Studies (GWAS) using data generated by Allelotyping and by individual Genotyping
No full textGenome-wide association studies (GWAS) are used to identify genetic markers linked with at least partially heritable diseases or phenotypes without prior knowledge of any disease-associated genetic loci. In summer 2008, all individuals of the population based cohort Study of Health in Pomerania (SHIP) were individually genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0 microarray. The aim of this work was to establish an efficient workflow for GWAS using the more than 4000 individually genotyped samples of the SHIP cohort as well as pooled samples, focusing exclusively on analyzing genetic variations based on single nucleotide polymorphisms (SNPs). Firstly, an optimal array platform for the genotyping analysis had to be chosen that detected most of the available genetic variants at a high level of accuracy. Secondly, extensive quality controls had to be performed starting from DNA extraction and including tests of the generated array data by the analysis software to obtain the most reliable data for the subsequent association studies. For the identification of loci with smaller genetic influences, individual cohorts were meta-analyzed in large nationally and internationally organized consortia (e.g. CHARGE, BPGen, HaemGen, GIANT, CKD Gen). To participate in those meta-analyses, a comparable common set of genetic data had to be generated. This was done by imputation of the data generated by individual array-based genotyping on the basis of a reference panel using chromosomal linkage information. Due to the extensive phenotype information in the SHIP study, it was possible to perform many genome-wide discovery analyses and replication studies of possible susceptibility loci in a short time once the genetic data was available and processed. This resulted in the necessity to set up an efficient workflow for storing the huge amount of genetic data, converting it into different formats readable for specific analysis software, performing the association analyses and processing the results into a human-readable and clear format. This included replications, GWAS and meta-analyses of several cohorts. Many susceptibility loci were newly identified in different association studies with the SHIP data included and were subsequently published. In this work, genetic association studies with the SHIP data included were performed and published on blood pressure, uric acid concentrations, cardiac structure and function, lipid metabolism, hematological parameters, kidney functions, smoking quantity, circulating IGF-I and IGFBP-3 concentrations and thyroid volume including the risk of goiter development. Besides the SHIP cohort, there was a need to use other, especially patient cohorts for GWAS. Since no genotype information from these patient cohorts was available and the individual genotyping of many probands is still expensive and therefore often not affordable, we established the cost-effective allelotyping method that relied on pooling of DNA samples prior to the hybridization with microarrays. After estimating the pooling-specific error of a case-control allelotyping study, the allelotyping approach was used for identifying genetic susceptibility loci associated with aggressive periodontitis. If not referring to work of collaborators, all statistical analyses, data handling and in silico work concerning the SHIP data described in this context was performed by the author of this dissertation.Genomweite Assoziationsstudien (GWAS) werden verwendet, um genetische Marker zu identifizieren, die mit zumindest teilweise vererbbaren Krankheiten oder Phänotypen assoziiert sind, ohne dabei vorab Informationen von bekannten krankheits-assoziierten genetischen Loci zu berücksichtigen. Im Sommer 2008 wurden alle Personen der bevölkerungsbasierten Kohorte Study of Health in Pomerania (SHIP) individuell mit Hilfe des Affymetrix Genome-Wide Human SNP Array 6.0 genotypisiert. Das Ziel dieser Arbeit war es, einen effizienten Workflow für GWAS basierend auf den mehr als 4000 einzeln genotypisierten Probanden der SHIP Kohorte sowie gepoolten DNA-Proben zu schaffen, wobei sich ausschließlich auf die Analyse genetischer Variationen von Einzelbasen-Polymorphismen (SNPs) beschränkt wurde. Zuerst mußte eine optimale Array-Plattform für die Genotypisierung ausgewählt werden, die die meisten bekannten genetischen Varianten mit hoher Genauigkeit detektieren kann. Zweitens mußten umfangreiche Qualitätskontrollen durchgeführt werden, beginnend bei der DNA-Extraktion bis hin zu Tests der durch die Analyse-Software erzeugten Array-Daten, um verlässliche Daten für die nachfolgenden Assoziationsstudien zu erhalten. Für die Identifizierung von Loci mit kleineren genetischen Einflüssen wurden Ergebnisse einzelner Kohorten in großen national und international organisierten Konsortien meta-analysiert (z.B. CHARGE, BPGen, HaemGen, GIANT, CKD Gen). Zur Teilnahme an diesen Meta-Analysen, mußte eine gemeinsame Basis genetischer Daten erzeugt werden. Dieses wurde durch sogenannte Imputation der Daten der einzelnen Array-basierten Genotypisierungen auf der Grundlage eines Referenz-Panels unter Berücksichtigung chromosomaler Kopplungsinformationen durchgeführt. Aufgrund der umfangreichen Phänotypinformationen der SHIP-Studie war es möglich, viele genomweite Analysen und Replikationsstudien zur Endeckung genetischer Anfälligkeits-Loci in kurzer Zeit durchzuführen, sobald die genetischen Daten zur Verfügung standen. Dafür war es notwendig, einen effizienten Workflow zur Speicherung der enormen Menge genetischer Informationen, deren Konvertierung in andere Formate welche lesbar für die spezielle Analyse-Software sind, die Durchführung der Assoziationsstudien und die Aufarbeitung der Ergebnisse in ein lesbares und übersichtliches Format zu erstellen. Dazu gehörten Replikationen, GWAS und Meta-Analysen von mehreren Kohorten. Viele neue Anfälligkeits-Loci konnten dabei in verschiedenen Assoziationsstudien unter Einbeziehung der SHIP-Daten identifiziert und anschließend veröffentlicht werden. In dieser Arbeit sind genetische Assoziationsstudien aufgeführt, die basieren auf Blutdruckdaten, Harnsäure-Konzentration, Herz-Struktur und -funktion, Fettstoffwechsel, hämatologischen Parametern, Nierenfunktion, Rauchen, IGF-I und IGFBP-3-Konzentrationen und Schilddrüsen-Volumen einschließlich des Risikos der Kropfbildung unter Einbeziehung der SHIP-Daten durchgeführt und veröffentlicht wurden. Neben der SHIP Kohorte gab es die Notwendigkeit GWAS in anderen Gruppen, besonders in Patientengruppen durchzuführen. Da keine Genotypinformationen aus diesen Patientengruppen zur Verfügung standen und die individuelle Genotypisierung von vielen Probanden noch teuer und daher oft nicht erschwinglich war, haben wir die kostengünstige Allelotypisierungs-Methode, die auf dem Poolen von DNA-Proben vor der Hybridisierung mit Microarrays basiert, umgesetzt. Nach Schätzung des pooling-spezifischen Fehlers anhand einer Fall-Kontroll-Allelotypisierungsstudie, wurde der Allelotypisierungsansatz zur Ermittlung genetischer Anfälligkeits-Loci, welche mit aggressiver Parodontitis assoziiert sind, angewendet. Falls nicht auf die Arbeit von Kooperatoren referenziert wurde, sind alle hier beschriebenen statistischen Analysen, die Datenverarbeitung und die in silico Arbeit basierend auf den SHIP-Daten vom Autor dieser Dissertation durchgeführt worden
Interactions Between Genetic Variants in Glucose Transporter Type 9 (SLC2A9) and Dietary Habits in Serum Uric Acid Regulation
No full textAim To investigate possible interactions between genetic
variants in glucose transporter type 9 (SLC2A9) gene and
dietary habits in serum uric acid regulation.
Methods Participants for this study were recruited from
two isolated Croatian island communities of Vis (n = 918)
and Korčula (n = 898). Three single nucleotide polymorphisms
(SNP) from the SLC2A9 gene (rs1014290, rs6449213,
rs737267) were correlated with dietary habits and uric
acid.
Results A significant decrease in uric acid levels was recorded
with increasing consumption of milk, sour cream,
duck and turkey, and eggs. The only significant interaction
was found between potato consumption and rs737267
and a near-significant interaction was found between soft
drinks and rs1014290 (interaction P = 0.068). Increased
consumption of soft drinks interacting with the TT genotype
at rs1014290 increased serum uric acid. No significant
interactions were observed between food products consumption
and rs6449213.
Conclusion There is a certain extent of interaction between
SLC2A9 and dietary patterns in serum uric acid determination.
The metabolic effect of soft drinks seems to
be determined by the underlying genotype of rs1014290
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