Genetische Mechanismen der Gewichtsregulation : genomweite Ansätze und Kandidatengenstudien
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.