Supervisor: TÜ MRI professor Andres Metspalu.
Opponent: Professor Tiina Paunio, Helsinki Ülikool, Soome Vabariik.
Human complex traits arise from the new mutations as well as from the interplay between the existing genetic variants and exposure to environmental conditions. The ultimate goals of human genetics are to understand the genetic architecture of complex traits and transfer the genetic findings into medical field in order to improve disease diagnosis and treatment. The draft sequence of the human genome has lead to development of high-throughput genotyping techniques that enable cost-effective detection of millions of DNA sequence variants in large numbers of samples. These advances have made it possible to increase the number of validated complex human trait-associated loci to 3,000 independent genetic variants related to more than 600 distinct traits and diseases. A single sequence variant usually explains less than 1% of the phenotypic variance or genetic predispositions and hundreds of thousands of samples must be pooled in GWAS meta-analyses to detect statistically sound associations. The Estonian Biobank, which includes a wide range of health information, biological samples, and high-resolution genomics data for more than 50,000 samples from the Estonian population, is a valuable resource for human genetic research. The aim of the current dissertation was to fill in the gaps in the knowledge of the genetic structure of northeastern European popu¬lations using the whole-genome SNP allele frequency data. The results revealed that Finns positioned distantly from Swedes and the other northeastern Europeans, while Estonians clustered next to their geographical neighbors (Latvians, Lithuanians and northwestern Russians), and demonstrated, that the Estonian Biobank samples could be analyzed together with the other cohorts of European ancestry in large-scale gene discovery studies. Two novel associations between a complex trait and a DNA sequence variant were established. In summary, the results of this study demonstrated the importance of the whole-genome genotyping array data in detecting the genetic structure and seeking the DNA sequence variants that underlie the dynamic complexity of human phenotypes.