Linkage disequilibrium mapping in isolated populations: The example of Finland revisited

Abstract

Linkage disequilibrium analysis can provide high resolution in the mapping of disease genes because it incorporates information on recombinations that have occurred during the entire period from the mutational event to the present. A circumstance particularly favorable for high-resolution mapping is when a single founding mutation segregates in an isolated population. We review here the population structure of Finland in which a small founder population some 100 generations ago has expanded into 5.1 million people today. Among the 30-odd autosomal recessive disorders that are more prevalent in Finland than elsewhere, several appear to have segregated for this entire period in the ''panmictic'' southern Finnish population. Linkage disequilibrium analysis has allowed precise mapping and determination of genetic distances at the 0.1-cM level in several of these disorders. Estimates of genetic distance have proven accurate, but previous calculations of the confidence intervals were too small because sampling variation was ignored. In the north and east of Finland the population can be viewed as having been ''founded'' only after 1500. Disease mutations that have undergone such a founding bottleneck only 20 or so generations ago exhibit linkage disequilibrium and haplotype sharing over long genetic distances (5-15 cM). These features have been successfully exploited in the mapping and cloning of many genes. We review the statistical issues of fine mapping by linkage disequilibrium and suggest that improved methodologies may be necessary to map diseases of complex etiology that may have arisen from multiple founding mutations.

Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A→G mutation of the untranslated RMRP

“…As an independent observation, the birthplaces of the great-grandparents of CHH patients are distributed in the early and late settlement regions relatively evenly, and strengthen the assumption that the major mutation was present at the time of the beginning of the population expansion some 80 -100 generations ago. 2,17 Similarly, our haplotype data, and the distribution of different mutations in Finland, allow us to assume that the four Finnish minor mutations are younger than the major mutation and that the local enrichment of CHH in the western Finland is, at least in part, due to the enrichment of the rare mutations in that region. The Finnish major mutation is also the most common mutation (48%) among the CHH patients in 44 families from other countries.…”

Detection of the founder effect in Finnish CADASIL families

“…In Finland, due to the population history there are founder effects in many genetic disorders, 25 for example in lysinuric protein intolerance (LPI) 26 and aspartylglucosaminuria (AGU). 27 Furthermore, the study of Finnish, Swedish and Norwegian patients with Kennedy disease (spinal-bulbar muscular atrophy, SBMA) revealed a Fenno-Scandinavian founder effect.…”

Genetic markers and population history: Finland revisited

“…Owing to advantageous features in its genetic architecture, for example, overall homogeneity, reduced diversity and increased linkage disequilibrium, the Finnish population is considered as a promising target for gene mapping studies. 2,3 Recent analyses have, nevertheless, suggested a substantial geographical structure in the genetic diversity of the Finns. 4 -7 The uniqueness of the Finnish genetic architecture has been explained by a series of founder effects and a subsequent drift in local subisolates.…”