Mapping genetic diseases in northern Sweden

Abstract: The population of northern Sweden has previously been shown to be well suited for the mapping of monogenic diseases. In this thesis we have tested the hypothesis that this population could also be used for efficient identification of risk genes for common diseases. In Paper I we have hypothesised that despite the admixture of Swedish, Finnish and Sami, the northern Swedish population consists of sub-populations geographically restricted by the main river valleys running through the region. This geographic isolation, in combination with founder effects and genetic drift, could represent a unique resource for genetic studies. On the other hand, it also underlines the importance of accounting for this e.g. in genetic association studies. To test this hypothesis, we studied the patterns of marriage within and between river valley regions and compared allelic frequencies of genetic markers between these regions. The tendency to find a spouse and live in the river valley where one was born is strong, and allelic frequencies of genetic markers vary significantly between adjacent regions. These data support our hypothesis that the river valleys are home to distinct sub-populations and that this is likely to affect mapping of genetic diseases in these populations. In Paper II, we tested the applicability of the population in mapping HSAN V, a monogenic disease. This disease was identified in only three consanguineous individuals suffering from a severe loss of deep pain perception and an impaired perception of heat. A genome-wide scan combined with sequencing of candidate genes resulted in the identification of a causative point mutation in the nerve growth factor beta (NGFB) gene. In Paper III, a large family with multiple members affected by familial forms of type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis (AITD) was studied. This syndrome was mapped to the IDDM12 region on 2q33, giving positive lodscores when conditioning on HLA haplotype. The linkage to HLA and to the IDDM12 region thus confirmed previous reports of linkage and/or association of T1DM and AITD to these loci and provided evidence that the same genetic factors may be mediating these diseases. This also supported the feasibility of mapping complex diseases in northern Sweden by the use of familial forms of these diseases. In Paper IV, we applied the same approach to study type 2 diabetes mellitus (T2DM). A non-parametric genome-wide scan was carried out on a family material from northern Sweden, and linkage was found to the calpain-10 locus, a previously described T2DM-susceptibility gene on 2q37. Together, these findings demonstrate that selecting for familial forms of even complex diseases, and choosing families from the same geographical region can efficiently reduce the genetic heterogeneity of the disease and facilitate the identification of risk genes for the disease.