Genetic mechanisms of body weight regulation: genome-wide approaches and candidate gene studies

The overall objective of this thesis was to study genetic mechanisms of body weight regulation. Two genome-wide approaches to identify chromosomal regions/candidate genes/genetic variants involved in body weight regulation were applied. Saar et al. (2003) presented the first genome-wide linkage scan for early onset obesity and detected suggestive evidence for linkage. In contrast, the first genome-wide association study for early onset obesity presented in Hinney et al. (2007) led to the re-identification of FTO, the currently best supported candidate gene for obesity. Thus, our investigation underlines two things: first, GWAs are in principle suitable to detect genes with small to modest genetic effect sizes, and second, with our relatively small but well defined sample of cases and controls it is possible to detect the same effects which required genotyping of several thousand population based unselected probands for body weight. Moreover, this thesis comprised the examination of three candidate genes for obesity (BDNF, GLUT4 and DGAT). Additionally, we observed that carriers of functionally relevant MC4R mutations are able to reduce their body weight, but that they seem to have difficulties to sustain this weight loss over time. Common obesity is caused by a complex interplay of genetic background and environmental factors. While monogenic forms of obesity are well understood, GWAs now seem to offer the option to detect oligo- and polygenes. As these genes are typically characterized by small to modest genetic effect sizes but are more common they might be more important than monogenes with regard to clinical implications. In sum, this work is part of a puzzle that might lead to evidence-based, personalized medicine which will be based on a solid scientific base by investigating the molecular genetic mechanisms of body weight regulation with regard to confirmed findings in independent large samples and by more carefully addressing methodological flaws

Non-replication of an association of CTNNBL1 polymorphisms and obesity in a population of Central European ancestry

<p>Abstract</p> <p>Background</p> <p>A recent genome-wide association (GWA) study of U.S. Caucasians suggested that eight single nucleotide polymorphisms (SNPs) in <it>CTNNBL1 </it>are associated with obesity and increased fat mass. We analysed the respective SNPs in data from our previously published GWA for early onset obesity (case-control design), in GWA data from a population-based cohort of adults, and in an independent family-based obesity study. We investigated whether variants in <it>CTNNBL1 </it>(including rs6013029) and in three other genes (<it>SH3PXD2B</it>, <it>SLIT3 </it>and <it>FLJ42133</it>,) were associated with obesity.</p> <p>Methods</p> <p>The GWA studies were carried out using Affymetrix^®SNP Chips with approximately 500,000 markers each. In the families, SNP rs6013029 was genotyped using the TaqMan^®allelic discrimination assay. The German case-control GWA included 487 extremely obese children and adolescents and 442 healthy lean individuals. The adult GWA included 1,644 individuals from a German population-based study (KORA). The 775 independent German families consisted of extremely obese children and adolescents and their parents.</p> <p>Results</p> <p>We found no evidence for an association of the reported variants in <it>CTNNBL1 </it>with early onset obesity or increased BMI. Further, in our family-based study we found no evidence for over-transmission of the rs6013029 risk-allele T to obese children. Additionally, we found no evidence for an association of <it>SH3PXD2B</it>, <it>SLIT3 and FLJ42133 </it>variants in our two GWA samples.</p> <p>Conclusion</p> <p>We detected no confirmation of the recent association of variants in <it>CTNNBL1 </it>with obesity in a population of Central European ancestry.</p

Mutation screen and association studies in the Diacylglycerol O-acyltransferase homolog 2 gene (DGAT2), a positional candidate gene for early onset obesity on chromosome 11q13

<p>Abstract</p> <p>Background</p> <p><it>DGAT2 </it>is a promising candidate gene for obesity because of its function as a key enzyme in fat metabolism and because of its localization on chromosome 11q13, a linkage region for extreme early onset obesity detected in our sample.</p> <p>We performed a mutation screen in 93 extremely obese children and adolescents and 94 healthy underweight controls. Association studies were performed in samples of up to 361 extremely obese children and adolescents and 445 healthy underweight and normal weight controls. Additionally, we tested for linkage and performed family based association studies at four common variants in the 165 families of our initial genome scan.</p> <p>Results</p> <p>The mutation screen revealed 15 DNA variants, four of which were coding non-synonymous exchanges: p.Val82Ala, p.Arg297Gln, p.Gly318Ser and p.Leu385Val. Ten variants were synonymous: c.-9447A > G, c.-584C > G, c.-140C > T, c.-30C > T, IVS2-3C > G, c.812A > G, c.920T > C, IVS7+23C > T, IVS7+73C > T and *22C > T. Additionally, the small biallelic trinucleotide repeat rs3841596 was identified. None of the case control and family based association studies showed an association of investigated variants or haplotypes in the genomic region of <it>DGAT2</it>.</p> <p>Conclusion</p> <p>In conclusion, our results do not support the hypothesis of an important role of common genetic variation in <it>DGAT2 </it>for the development of obesity in our sample. Anyhow, if there is an influence of genetic variation in <it>DGAT2 </it>on body weight regulation, it might either be conferred by the less common variants (MAF < 0.1) or the detected, rare non-synonymous variants.</p

Genome Wide Association (GWA) Study for Early Onset Extreme Obesity Supports the Role of Fat Mass and Obesity Associated Gene (FTO) Variants

Background. Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity. Methodology/Principal Findings. a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency $10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13610 27, corrected p = 0.0494; odds ratio (OR)CT 1.67, 95 % confidence interval (CI) 1.22–2.27; OR TT 2.76, 95 % CI 1.88–4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p,0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium

Технические особенности эксплуатации магистральных нефтепроводов в условиях Крайнего Севера

Объект исследования – магистральные нефтепроводы, расположенные в условиях Крайнего Севера. Целью работы является исследование особенностей эксплуатации и разработка рекомендаций для обеспечения надежности магистральных нефтепроводов в условиях Крайнего СевераThe object of the research is the main oil pipelines located in the Far North. The aim of the work is to study the features of operation and development of recommendations to ensure the reliability of the maintec main oil pipelines in the Far North

Eating disorders: the current status of molecular genetic research

Anorexia nervosa (AN) and bulimia nervosa (BN) are complex disorders characterized by disordered eating behavior where the patient’s attitude towards weight and shape, as well as their perception of body shape, are disturbed. Formal genetic studies on twins and families suggested a substantial genetic influence for AN and BN. Candidate gene studies have initially focused on the serotonergic and other central neurotransmitter systems and on genes involved in body weight regulation. Hardly any of the positive findings achieved in these studies were unequivocally confirmed or substantiated in meta-analyses. This might be due to too small sample sizes and thus low power and/or the genes underlying eating disorders have not yet been analyzed. However, some studies that also used subphenotypes (e.g., restricting type of AN) led to more specific results; however, confirmation is as yet mostly lacking. Systematic genome-wide linkage scans based on families with at least two individuals with an eating disorder (AN or BN) revealed initial linkage regions on chromosomes 1, 3 and 4 (AN) and 10p (BN). Analyses on candidate genes in the chromosome 1 linkage region led to the (as yet unconfirmed) identification of certain variants associated with AN. Genome-wide association studies are under way and will presumably help to identify genes and pathways involved in these eating disorders. The elucidation of the molecular mechanisms underlying eating disorders might improve therapeutic approaches

vorgelegt dem Rat der Biologisch-Pharmazeutischen Fakultät der Friedrich-Schiller-Universität Jena von

geboren am 26.05.1978 in DresdenGenetic mechanisms of body weight regulation: Genome-wide approaches and candidate gene studies Dissertatio

Traffic perception and hazard avoidance - Foundations and possibilities for implementation in novice driver preparation

Der vorliegende Innovationsbericht beschreibt die Forschungs- und Entwicklungsschwerpunkte der TÜV | DEKRA arge tp 21 im Hinblick auf das Fahrerlaubnisprüfungssystem für den Zeitraum 2011 - 2014. Diese lagen (1) in der Aufbereitung wissenschaftlicher Grundlagen zur Vermittlung und Erfassung von Kompetenzen im Bereich der Verkehrswahrnehmung und Gefahrenvermeidung bei Fahranfängern, (2) in der Evaluation und Weiterentwicklung der Theoretischen Fahrerlaubnisprüfung und (3) in Forschungs- und Entwicklungsarbeiten zur Optimierung der Praktischen Fahrerlaubnisprüfung sowie (4) in der Beschreibung des fahrzeugtechnischen Wandels und seiner Bedeutung für die Fahrausbildung und Fahrerlaubnisprüfung. Zu (1): Kompetenzdefizite von Fahranfängern gegenüber erfahrenen Fahrern in der Verkehrswahrnehmung und Gefahrenvermeidung sind durch eine Vielzahl empirischer Studien belegt. Die systematische Vermittlung und Aneignung entsprechender Fähigkeiten im Vorfeld der selbständigen Verkehrsteilnahme erscheint deshalb vielversprechend für die Verringerung fahranfängertypischer Unfallrisiken. Der Entwicklung diesbezüglicher Ausbildungs- und Prüfungskonzepte muss jedoch zunächst eine Beschreibung der zugrunde liegenden psychologischen Konstrukte vorausgehen. Im Berichtszeitraum wurden dazu die relevanten wahrnehmungs- und verkehrspsychologischen Grundlagen aufgearbeitet. Weiterhin wurden die international im Fahrerlaubniswesen bereits praktizierten innovativen PC-basierten Prüfungsansätze wie auch experimentelle Untersuchungen aus der "Hazard Perception"-Forschung analysiert. Schließlich wurden Lehr-Lernangebote für Fahranfänger recherchiert. Mit den im Bericht vorgelegten Ergebnissen wurde der theoretische Grundstein für die künftige Verankerung der Verkehrswahrnehmung und Gefahrenvermeidung in der Fahranfängervorbereitung gelegt. Hieran wird nun die Erarbeitung innovativer Lernangebote und Prüfungsaufgaben für Fahranfänger anschließen. Zu (2): Die Arbeiten zur Theoretischen Fahrerlaubnisprüfung umfassten die Evaluation von Prüfungsaufgaben und Paralleltests sowie auch weiterführende empirische Untersuchungen zur Bearbeitung anlassbezogener Fragestellungen (u. a. Modellrechnungen zur Erarbeitung von empirisch gestützten Empfehlungen für eine optimierte Prüfungsbewertung). Weiterhin wurden 2014, d. h. zum Ende des Berichtszeitraums, erstmals Aufgaben mit dynamischen Situationsdarstellungen eingesetzt. Die vorbereitenden Forschungs- und Entwicklungsarbeiten werden im Bericht überblicksartig dargestellt. Nicht zuletzt werden erste Ergebnisse der empirischen Erprobung innovativer Aufgabenformate diskutiert, bei denen neuartige Formen der Antworteingabe (Tastendruck, Pedal) und der Leistungsbewertung (Reaktionszeit) verwendet wurden. Die skizzierten Forschungsarbeiten lassen erkennen, dass seit einigen Jahren die Vorteile des Prüfmediums "Computer" erfolgreich genutzt werden. Sie zeigen jedoch auch, dass die PC-gestützte Prüfung weitere Potentiale " insbesondere im Bereich der Aufgabenentwicklung und Testkonstruktion " birgt, die es zukünftig auszuschöpfen gilt. Zu (3): Die Arbeiten zur Praktischen Fahrerlaubnisprüfung waren im Wesentlichen durch drei verbundene Projekte gekennzeichnet: Das BASt-Projekt "Optimierung der Praktischen Fahrerlaubnisprüfung" diente der Erarbeitung methodischer Grundlagen (es begann 2008 und endete im ersten Jahr des Berichtszeitraumes). Als zweites folgte eine von der TÜV | DEKRA arge tp 21 durchgeführte Machbarkeitsstudie (2011 bis 2012) zur Untersuchung der Praktikabilität einer elektronischen Prüfungsdokumentation ("e-Prüfprotokoll"). Das BASt-Projekt "Revision zu einer optimierten Praktischen Fahrerlaubnisprüfung" stellt schließlich das dritte Projekt dar (es begann im Jahr 2013 und wird über den Berichtszeitraum hinaus bis 2015 fortgeführt). Es dient dazu, die Inhalte, Verfahren und Abläufe der Prüfung (einschließlich Verfahrensweisen zu einer kontinuierlichen Evaluation) bis hin zur Einsatzreife weiterzuentwickeln und in ausgewählten Modellregionen zu erproben. Mit einer bundesweiten Implementierung der erarbeiteten Standards würde gewährleistet, dass die Entscheidung über die Zulassung zum motorisierten Straßenverkehr künftig auf einer differenzierten Fahrkompetenzeinschätzung basiert und festgestellte Kompetenzdefizite systematisch erfasst und zurückgemeldet werden " dies lässt eine verbesserte Sicherheitswirksamkeit der Praktischen Fahrerlaubnisprüfung erwarten. Zu (4): Fahrzeugtechnische Innovationen " seien es Fahrerassistenzsysteme, Antriebskonzepte ("e-Mobilität") oder das (teil-)automatisierte Fahren " kommen in immer kürzeren Abständen auf den Markt. Diese Entwicklungen sind mit veränderten Anforderungen an das Fahren verbunden und haben daher maßgeblichen Einfluss auf den Erwerb, die Überpruefung und den Erhalt von Fahrkompetenz. Im Bericht werden die daraus resultierenden zukünftigen Aufgabenstellungen für die Technischen Prüfstellen skizziert.The present innovation report describes key topics addressed in the relevant research and development activities of the TÜV | DEKRA arge tp 21 working group during the report period from 2011 to 2014. Such essential aspects were (1) presentation of the scientific foundations for development and assessment of novice driver competence relating to traffic perception and hazard avoidance, (2) evaluation and further development of the theoretical driving test, (3) research and development work aimed at optimisation of the practical driving test, and (4) description of the continuing advances in vehicle engineering and their significance for both driver training and testing. Re (1): Numerous empirical studies point to the competence deficits displayed by novice drivers compared to more experienced drivers in respect of traffic perception and hazard avoidance. The systematic development and acquisition of corresponding skills in advance of their solo participation in road traffic thus appears promising as a means to reduce novice-typical accident risks. The development of training and test concepts addressing traffic perception and hazard avoidance, however, requires prior description of the underlying psychological constructs. During the report period, the relevant perceptual and traffic psychology foundations were analysed alongside innovative, computer-based approaches which have already been implemented in international driving licence testing and experimental studies from the field of hazard perception research. A further study was conducted to survey teaching and learning offers for novice drivers. The results presented in the report provide a theoretical basis for the future anchoring of traffic perception and hazard avoidance in the system of novice driver preparation. This work must now be continued with the elaboration of innovative learning offers and corresponding assessment tasks for novice drivers. Re (2): The work on the theoretical driving test referred to the evaluation of individual test items and their assignment to parallel tests, as well as further empirical studies to answer specifically arising questions (e.g. model calculations to enable the elaboration of empirically founded recommendations on optimisation of the test assessment). In 2014, i.e. at the end of the current report period, furthermore, test items based on dynamic situation presentations were used for the first time. The report provides an overview of the preparatory research and development work. Last but not least, initial results from the empirical testing of innovative task formats implementing new forms of response input (keyboard, foot pedal) and performance assessment (reaction time) are discussed. The research and development work outlined in the report illustrates how benefits of the new test medium "computer" have been utilised successfully for a number of years. It is equally evident, however, that significant further potential is embodied in computer-based testing " especially in respect of task development and test design; the objective for the future must be to exploit this potential. Re (3): The research work on development of the practical driving test was essentially dominated by three projects: The BASt project "Optimisation of the Practical Driving Test" served to elaborate methodical foundations (it began in 2008 and was brought to conclusion during the first year of the report period). The second project was a feasibility study to investigate the practicability of an electronic test report, which was conducted by the TÜV | DEKRA arge tp 21 working group (2011 to 2012). The BASt project "Revision Project on an Optimised Practical Driving Test", finally, was commenced in 2013 and is scheduled to continue beyond the current report period into 2015. Its purpose is to continue development of the corresponding contents, methods and procedures (including methods which will enable continuous evaluation). Once ready for actual use, the results are to be tested in selected model regions. Subsequent nationwide implementation of the elaborated standards would ensure that decisions on the eligibility to participate in motorised road traffic are based on a differentiated assessment of driving competence. At the same time, observed competence deficits could be recorded systematically and communicated to the driving license applicant. This can be expected to strengthen the safety-enhancing impact of the practical driving test. Re (4): Technical innovations in vehicle engineering " whether driver assistance systems, new drive concepts ("e-mobility") or solutions for (partially) automated vehicle control " are entering the market at ever shorter intervals. Such developments bring changes in the demands placed on drivers and thus exert a decisive influence on the acquisition, assessment and upholding of driving competence. The report outlines the tasks resulting for the Technical Examination Centres in the future

Genome scan for childhood and adolescent obesity in German families

Objective: Several genome scans have been performed for adult obesity. Because single formal genetic studies suggest a higher heritability of body weight in adolescence and because genes that influence body weight in adulthood might not be the same as those that are relevant in childhood and adolescence, we performed a whole genome scan. Methods: The genome scan was based on 89 families with 2 or more obese children (sample 1). The mean age of the index patients was 13.63 ± 2.75 years. A total of 369 individuals were initially genotyped for 437 microsatellite markers. A second sample of 76 families was genotyped using microsatellite markers that localize to regions for which maximum likelihood binomial logarithm of the odd (MLB LOD) scores on use of the concordant sibling pair approach exceeded 0.7 in sample 1. Results: The regions with MLB LOD scores >0.7 were on chromosomes 1p32.3-p33, 2q37.1-q37.3, 4q21, 8p22, 9p21.3, 10p11.23, 11q11-q13.1, 14q24-ter, and 19p13-q12 in sample 1; MLB LOD scores on chromosomes 8p and 19q exceeded 1.5. In sample 2, MLB LOD scores of 0.68 and 0.71 were observed for chromosomes 10p11.23 and 11q13, respectively. Conclusion: We consider that several of the peaks identified in other scans also gave a signal in this scan as promising for ongoing pursuits to identify relevant genes. The genetic basis of childhood and adolescent obesity might not differ that much from adult obesity