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.

Figure 1

Map of Finland showing the approximate extent of the early settlement (old Finland) in the south and west in which the population began to expand some 2,000–2,500 years ago, and the area of late settlement (new Finland) in the north and east in which population expansion started mainly after 1500. (Adapted from ref. .)

Figure 2

Map of Finland showing the birthplaces of all known great-grandparents of patients with DTD studied. By using the birthplaces of great-grandparents putative biases stemming from the recent move of people from the north and east of the country to the south and west is avoided. However, of eight great-grandparents only two are actual carriers. See Fig. 5 for further comments. The distribution of birthplaces shown here is mainly in old Finland, suggesting that the putative ancestral founding DTD mutation was present in the population at the beginning of its expansion, some 2,000 to 2,500 years ago. Note also at least two local enrichments that are typical and stem from the existence, even in the panmictic older Finnish population of county-sized regional isolates in which local founder effects and genetic drift can occur. (Adapted from ref. .)

Figure 3

Diagram of the CSTB region on chromosome 21q. The x-axis shows the location and physical distances (in kb) between five polymorphic markers. • indicate the degree of linkage disequilibrium (expressed as p_excess) calculated between EPM1 and the marker. Before CSTB was found (its location is shown in red), a minimal critical region (shown in blue) was defined based on the analysis of historical recombinations in the haplotypes of 88 EPM1-carrying chromosomes. The green arrow shows the point of highest multipoint linkage disequilibrium (z = 62.13) using these markers.

Figure 4

Map of Finland showing birthplaces of grandparents (red) and parents (blue) of 34 patients with CLD. The distributions are very similar, showing that recent moves from the eastern and north-central parts of the country to the south and west that would significantly distort the distribution have not occurred. Birthplaces are almost entirely confined to new Finland that is, regions populated after the 1500s. (Adapted from ref. .)

Figure 5

Map of Finland showing birthplaces of ancestors of patients with HNPCC. The dotted line depicts the approximate border between old and new Finland. Each symbol depicts a kindred with several HNPCC patients. All of the kindreds share the same genomic deletion of exon 16 of the MLH1 gene. Based on linkage disequilibrium with numerous markers in and around the MLH1 gene, extensive haplotype conservation among kindreds marked in red suggests only a limited number of generations (perhaps 16) since founding. This finding is consistent with the population history of new Finland. In contrast, the two kindreds shown in blue share only a 2-cM core of the conserved haplotype with the other kindreds, suggesting a much older age of the mutation (perhaps 43 generations). This finding fits with their geographical location in old Finland. (Adapted from ref. .)