Fine-scale genetic structure and polygenic scores in Finland

Population genetics is today an essential part of the studies of human origin and history, as well as of the studies of disease genetics. Populations living apart from each other exhibit genetic variation and this variation between populations is called genetic structure. By studying the genetic structure around the world, it has become possible, for example, to elaborate on the migration patterns of modern humans from the African continent to the rest of the world during the last 100,000 years. In addition, the modern methods of population genetics have enabled a very detailed analysis of genetic structure and population history within single countries, but these methods have not yet been widely utilized in isolated populations such as in Finland. In medical genetics, the genetic background of diseases is routinely analyzed with a genome-wide association study (GWAS). In these studies, it is important to control for the genetic structure of the data appropriately, so that the genetic variation associated with the disease can be reliably distinguished from the general genetic variation associated with the genetic structure. The results of GWAS are used in research to predict the genetic disease risk of an individual using a polygenic score that summarizes the estimated genetic risk over multiple sites of the genome. Because of this summation, even a tiny bias in the GWAS results, due to the genetic structure, can lead to a significant bias in polygenic scores, which, in turn, can lead to incorrect conclusions especially in comparisons between populations. Therefore, understanding the genetic structure and its role in building polygenic scores is exceptionally important to properly understand both the benefits and limitations of polygenic scores in academic research and in future health-care applications. This doctoral thesis examined the fine-scale genetic structure and its role in the geographic distribution of polygenic scores in Finland. The first part of the thesis expanded the understanding of the genetic structure of Finland by determining the geographic border for the major genetic split between East and West Finland, and by identifying 17 previously unreported genetic fine-scale populations. The fine-scale populations were observed to be geographically clustered and to follow Finnish dialect regions. The second part of the thesis utilized the earlier results by building, based on the fine-scale genetic structure, reference groups to estimate the genetic ancestry profile of an individual within Finland. By estimating the genetic ancestry profiles for a set of individuals born between 1923 and 1987, this second study was able to map annual changes in the fine-scale genetic structure within 12 regions. The annual profiles matched well with the migration patterns of Karelian evacuees who were displaced by the war events between 1939 and 1945. The third part of the thesis assessed the role of the genetic split between East and West in the geographic distribution of the genetic risk of five complex diseases (coronary artery disease, rheumatoid arthritis, schizophrenia, ulcerative colitis, and Crohn’s disease) and three quantitative traits (height, body mass index, and waist-hip ratio) using polygenic scores. The third study demonstrated that most of the polygenic scores, that did show geographic variation, mirrored the genetic split between East and West Finland but also revealed bias associated with the genetic structure in Finland. This final study thus demonstrated two main points: first that polygenic scores are susceptible to genetic structure-related biases, even within a relatively homogeneous populations; and second that it is challenging to link population-genetic variation to geographic variation in disease incidence with the current methods. Overall, the results of this doctoral thesis update the current understanding of fine-scale genetic structure in Finland and its changes to meet the needs of modern genetics research. It also demonstrates, both for the scientific community and for the general public, the importance of understanding the genetic structure in the study of both population history and polygenic scores.