Finnish Disease Heritage

The Finnish disease heritage is a good example of how founder effects and genetic isolation have moulded the gene pool of this population. A group of 35 monogenic diseases are more frequent in Finland than in any other population. Several bottlenecks during population history and inhabitation of remote areas in the large country by small groups of settlers has caused enrichment of some disease causing genes and losses of others. Most of the diseases have an autosomal recessive mode of inheritance, while two are autosomal dominant and two X-chromosomal. Recent genetic studies have determined the gene involved and causative mutations for 29 diseases; one founder mutation accounts for 70 to 100 percent of these disease alleles.

Perheentupa’s steps. The timescale shows the year of first Finnish publication of the disease.
Scalable Version

Finnish Population History and Diseases
	The demographic history of Finland is typical of many isolates. A small number of original founders, subsequent isolation, rapid expansion and major bottlenecks have allowed genetic drift to mould the gene pool. The vast majority of Finns descend from two immigration waves occurring about 4,000 and 2,000 years ago. The earlier wave involved eastern Uralic speakers, and the later wave, Indo-European speakers from the south. Both Y-chromosomal haplotypes and mitochondrial sequences show the low genetic diversity among Finns compared with other European populations and confirm the long-standing isolation of Finland. The size of the founding population(s) is unknown, but as late as the twelfth century, the population of Finland was only about 50,000, as shown in the top figure. It reached 400,000 by the mid-seventeenth century, only to experience the great famine of 1696–1698, where one third of the population perished. Since then, the Finnish population has grown relatively rapidly from 250,000 at the beginning of the eighteenth century to its present figure of 5,100,000. Starting in the sixteenth century, during the reign of the Swedish King Gustavus of Vasa (1523–1560), internal migrations created regional subisolates (as shown in the bottom figure). The population spread from the early settlement region on the southern and western coastline towards the east and north. The subisolates in the late settlement region were established for the most part by groups of farmers originating from a small area of South Savo in southeastern Finland. They moved to the central, then western, and finally northern parts of the country, clearing the land by fire. Within a century, the inhabited land area of Finland doubled. Until the Second World War, many of these northeastern settlements grew rapidly without further immigration to supplement the descendants of their 40–60 founding families. The reign of Gustavus of Vasa also saw the establishment of a national system of population records, an important resource for later genetic studies of Finns. Using these records, many deceased individuals can be traced to common ancestors, especially in the subisolates of the late settlement region. Finland's demographic history has led to a unique catalogue of genetic diseases. Around 30, mostly recessive diseases, are highly enriched in Finland. Other diseases, such as phenylketonuria and cystic fibrosis, are almost non-existent. Molecular studies have exposed one major mutation (78–98% alleles) in most Finnish Mendelian diseases and have revealed long genetic intervals of linkage disequilibrium (LD) flanking the disease gene, with the length of the LD interval reflecting the age of the mutation.
This figure originally appeared in Peltonen L et al., Nature Reviews Genetics 1, 182-190 (2000).

Regional Distribution of the Diseases

The population history of Finland has led to an uneven regional distribution of the disease alleles. Internal movement in the last few decades has somewhat reduced this effect, but birthplaces of the patients’ grandparents represent a typical regional clustering (Norio R, 2003a).

This phenomenon has especially been studied in autosomal recessive disorders. For most diseases birthplaces are concentrated around the area of late settlement, populated from the 1500s. The example given in the figure 3 is the distribution in Mulibrey nanism (MUL). The other diseases in this group are APECED, COH1, CCD, CLD, CNA2, FSH-RO, GA, HLS, IOSCA, LCCS, LPI, NKH, PLOSL, SD, and USH3.

In the second group of diseases and the places of origin are distributed throughout the country, although some clustering can be seen in the late settlement area. This group is comprised of the most common diseases; CHH (see figure 4), AGU, CNF, CLN1, and EPM1.

In the third group the distribution is predominantly in the western early settlement area, and follows the population density of Finland. This may suggest that these disease alleles have spread without the effect of “late settlement”. This group consists of only two disorders, which are also quite common in other parts of Europe. The example given in the figure 5 is Meckel syndrome (MKS), and the other disease is diastrophic dysplasia (DTD).

The fourth group consists of two diseases that are strictly local, for which disease causing mutations have occured more recently. Northern epilepsy (EPMR) is found in the Kainuu region near the Eastern border, and the Finnish variant of late infantile neuronal ceroid lipofuscinosis (CLN5) in Southern Ostrobothnia.

Four autosomal recessive disorders, MEB, PEHO, RAPADILINO, and MGA1, form the fifth “atypical” group. The distribution of them does not overlap with the other diseases.

The two autosomal dominant (FAF, TMD) and two X-chromosomal (CHM, RS) disorders are also regionally concentrated. They haven’t been placed in these groups because they don’t need isolation to occur.

Geographic Distribution of Diseases

Fig. 4 Mulibrey nanism (MUL). Map by Reijo Norio, Suomi-neidon geenit.
Otava, Helsinki, 2000.

Fig. 5 Cartilage-hair hypoplasia (CHH). Map by Reijo Norio,
Suomi-neidon geenit. Otava, Helsinki, 2000.

Fig. 6 Meckel syndrome (MKS). Map by Reijo Norio, Suomi-neidon geenit.
Otava, Helsinki, 2000.

Fig. 7 Northern epilepsy (EPMR). Map by Reijo Norio, Suomi-neidon
geenit. Otava, Helsinki, 2000.

Key References

de la Chapelle A et al. Linkage disequilibrium mapping in isolated populations: the example of Finland revisited. Proc Natl Acad Sci USA. 1998 Oct 13;95(21):12416-23.

Kere J. Human population genetics: lessons from Finland. Annu Rev Genomics Hum Genet. 2001;2:103-28.

Norio R. Finnish Disease Heritage I: characteristics, causes, background. Hum Genet. 2003 May;112(5-6):441-56.

Norio R. Finnish Disease Heritage II: population prehistory and genetic roots of Finns. Hum Genet. 2003 May;112(5-6):457-69.

Norio R. The Finnish Disease Heritage III: the individual diseases. Hum Genet. 2003 May;112(5-6):470-526.

Peltonen L et al., Molecular genetics of the Finnish disease heritage. Hum Mol Genet. 1999;8(10):1913-23.