Researchers in Finland identified variations in DNA that might predispose certain individuals to disease

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A new study harnessed the unique genetic history of the people of Finland to identify variations in DNA that might predispose certain individuals to disease, whether or not they are Finnish themselves.

The study was conducted by researchers at Washington University School of Medicine in St. Louis, in collaboration with the University of California, Los Angeles; the University of Michigan and other institutions, including several partners in Finland.

The research, published July 31 in the journal Nature, identified 26 potentially harmful DNA variations relevant to cardiovascular and metabolic health.

For example, such variations might alter a person’s lifetime risk of developing obesity, diabetes or high cholesterol levels.

Though this analysis is just a starting point to delve more deeply into the health consequences of these types of DNA variants, the study is an important milestone in demonstrating the effectiveness of this population approach to genetic research.

Of the 26 DNA variations identified, 19 are either unique to Finnish individuals or over 20 times more frequent in Finland compared with elsewhere in Europe.

Without this unique population – isolated and relatively genetically similar – the researchers estimate they would need to sequence the DNA of hundreds of thousands to millions of people to find these same associations, rather than the relatively manageable 20,000 individuals analyzed in this study.

According to the investigators, this study is among the most comprehensive examinations of the impact of coding variation – DNA changes that impact protein structure and function – on measures of cardiovascular and metabolic health, an endeavor greatly facilitated by Finnish population history.

“The small population of people who first settled this part of the world – combined with relatively little immigration that would add variation to the gene pool – has pushed important genetic variants that first existed in the founding population to expand and become much more common than they would be elsewhere,” said first author Adam E. Locke, Ph.D., an assistant professor of medicine at Washington University School of Medicine in St. Louis. “Now we can delve into the patient data – which is extremely well-characterized through Finland’s national health-care system – to understand how these genetic variants influence overall health and disease risk in the people who have them.”

Finland is a relatively isolated country, and with two major population bottlenecks over its history, the Finnish people have DNA more similar to one another than people in many other parts of the world.

Such bottlenecks occur when a major event – perhaps a violent conflict, disease or natural disaster—causes a large drop in population.

The population that then expands after the event is more genetically similar than before.

The effect has produced a set of genetic diseases – called the Finnish Disease Heritage – that can occur anywhere but are much more common in Finland than in other European populations. Conditions listed on the Finnish Disease Heritage are caused by mutations in a single gene and often have severe effects on health.

Though many studies have employed the unique history of the Finnish people for genetic discovery, this is among the first to comprehensively examine the impact of rare, coding DNA variants – the kind that impact protein structure and function – on common conditions that typically involve more subtle changes in genetics than those driving the conditions of the Finnish Disease Heritage.

According to the researchers, some of the more intriguing DNA variants identified are associated with changes in cholesterol levels, differences in levels of amino acids in the blood – which, depending on the specific amino acids, can suggest a number of health problems, including liver or kidney dysfunction—and changes in height and body weight.

Locke said his work primarily is focused on data from Finland, but the researchers would like to expand this type of study to include similarly isolated populations of people from different parts of the world.

For example, communities of people living on islands such as Sardinia in Italy, Crete in Greece or the Samoan Islands in the South Pacific also might provide similarly genetically unique populations to study, and perhaps highlight some different yet universal aspects of human health.


Isolated populations may have a unique genetic background as, by chance, the founder population has initially had a certain assortment of gene variants which, again by chance, may have developed towards enrichment of some of the variants and disappearance of some others.

As the population size is small, the possible bottleneck events like epidemics, wars, or hunger have a more profound effect on the gene pool when compared to larger populations.

The isolation may be cultural as in the case of Ashkenazi Jews or geographical with Faroe Islands as an example.

In case of Finland, both geographical isolation due to the very Nordic position of the country and cultural isolation due to religious and language boundaries have caused enrichment of some disease-causing gene variants and losses of others (Norio et al. 1973).

The special genetic constitution of the Finnish population has had a profound effect on the research of genetics of both rare and common diseases as well as on some health care practices.

As genomic tools will be more widely used in the healthcare in the future, the unique genetic background of Finns and other isolated populations can be anticipated to offer exceptional possibilities for implementing genomic medicine at the population level.Go to:

The Finnish disease heritage

Traditionally, a group of 36 monogenic diseases which are more frequent in Finland than in any other population have been named the Finnish disease heritage (Norio, 2003b (III)).

All these diseases, most of which are autosomal recessive, with their major clinical and molecular findings are presented at www.findis.org.

This website focuses on updating what is known about the mutational background of those diseases.

However, in addition to enrichment of some monogenic diseases, there are other features related to the Finnish disease heritage as well.

Some autosomal recessive diseases which are rather prevalent in other Western and Nordic European countries are much less prevalent or practically lacking in Finland. For instance, the prevalence of cystic fibrosis is only about 1/10 of that in most of the neighboring countries (Kinnunen et al. 2005).

In some other diseases, as prevalent in Finland as elsewhere, the mutational background is different and more homologous in the Finnish population. Lynch syndrome with few founder mutations is a good example of this phenomenon (Lynch and de la Chapelle 1999).

Similarly, founder effect has influenced the assortment of variants associated with high or low risk for common multifactorial diseases. Genome-wide patterns of common genetic variation also reflect considerable population substructure in Finns (Jakkula et al. 2008).

This genetic substructure may explain differences in the regional prevalence of common diseases such as coronary heart disease (Aalto-Setälä et al. 1991; Tyynelä et al. 2010). Finally, the collection of the monogenic Finnish disease heritage cannot be considered complete and closed as new diseases following the same patterns of enriched founder mutations are still identified (Trotta et al. 2016). New diseases can be expected to be found especially among adults as the initial enthusiasm around the phenomenon was mainly among paediatricians.

Clinical identification of the diseases

During 1970–1980 clinical researchers, especially paediatricians and ophthalmologists identified several new disease phenotypes or too many cases of diseases already delineated elsewhere. It started to seem that the assortment of rare diseases, especially autosomal recessive ones, was unique in the Finnish population.

During a thorough genealogical study of one of those diseases, congenital nephrosis of Finnish type (MIM # 256300), Norio et al. (1964) realized that instead of several consanguineous marriages like first cousin marriages, as could have been expected as the disease was assumed to be autosomal recessive, there were numerous very remote connections between the parents but also between separate families in early generations even several hundreds of years back (Fig. ​(Fig.1).1).

This led to the understanding that this disease as well as several others was overrepresented in Finnish population and especially in certain regions of Finland because of our population history (Norio et al. 1973).

Due to the initially small population, an older founder mutation could, by chance, have been rather prevalent in the founder population of Finland. Later around the sixteenth century, the political decision to inhabit the empty inner land of Finland created a situation where a small sample of individuals became founders of a new regional population carrying their set of mutations with them.

As until recently people continued to live in their original rural areas and marry among the surrounding people, this led to a situation where the likelihood of marrying a distant relative was very high, nearly a rule, without the people recognizing that the marriage was actually consanguineous. The situation was accentuated by external forces like wars and periods of hunger creating bottleneck effects which still narrowed the gene pool in each region (Norio 2003a I).

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Fig. 1
Of the eight parents of four sibships with an autosomal recessive disorder belonging to the Finnish disease heritage, six have been shown using genealogic data from Church Records of Finnish Lutheran Church to descend from an individual who lived in that region some 400 years ago. The figure also shows several more recent connections between the families. Courtesy of Professor Reijo Norio

When this was understood, the concept of the Finnish disease heritage started to form. The criterion for a disease to be included in the list was that it should be more prevalent in Finland than elsewhere. However, there never was a strict rule defining how much more prevalent the disease had to be. This kind of rule would have actually been impossible as the epidemiology of rare diseases was and still is poorly known in most countries, including Finland, due to among other things, underdiagnosis. So some diseases maybe were included in the list with too loose criteria and some others were excluded with no good reason. In addition, two of the diseases are inherited in X-linked manner and two are autosomal dominant; for those diseases, the population history does not give similar logical explanation.

The diseases on the present official list can be grouped according to the main manifestations. Of them, 11 are progressive central nervous system diseases beginning usually in childhood, 5 are prenatally or neonatally fatal malformation syndromes, 5 are ophthalmological disorder, and 4 manifest with growth deficiency. Many feature multiple symptoms, for instance, Rapadilino patients are small, have several malformations and dysmorphic features and they also have increased risk for some types of malignancies (Siitonen et al. 2009). The diseases have been traditionally presented as “Perheentupa’s steps” as Professor Jaakko Perheentupa suggested this presentation to show how they, one by one during some decenniums, were identified and published as exceptional Finnish cohorts (Fig. ​(Fig.2).2). In the case of some of the diseases, the initially monotonous phenotype is evolving as today patients are not only detected by their symptoms (leading to targeted genetic testing) but via genomic sequencing of undiagnosed cases.

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Fig. 2
The collection of the diseases of the Finnish disease heritage is often presented as “Perheentupa’s Steps.” This way to illustrate the growing number of these diseases was first used by Professor Jaakko Perheentupa. Each disease is presented at the year when the first Finnish publication of the disease was published. The genes and founder mutations of all these diseases have been detected, nearly always by Finnish researchers. Courtesy of Dr. Teppo Varilo

Phenylketonuria (PKU) is an extreme example of the counter part of the Finnish disease heritage: the diseases that have an exceptionally low prevalence in Finland.

When PKU had been characterized, a search was organized among all institutions for mentally retarded in Finland at a time when it was a common practice to care for mentally retarded patients in institutions (Palo 1967).

About at the same time, 80,000 newborns were screened for PKU (Visakorpi et al. 1971).

Of these attempts to find PKU cases, it was concluded that PKU is much more rare in Finland than elsewhere; the estimated birth prevalence was between 1/100,000 and 1/200,000 while in the neighboring countries, the reported birth prevalence is much higher, about 1/6000 in Estonia (Ounap et al. 1998) and 1/15,800 in Sweden (Ohlsson A et al. 2016). For that reason, Finland offered neonatal screening only for hypothyreosis until very recently.


More information: Locke AE, Steinberg KM, Chiang CWK, Service SK, et al. Exome sequencing of Finnish isolates enhances rare-variant association power. Nature. July 31, 2019. DOI: 10.1038/s41586-019-1457-z , https://nature.com/articles/s41586-019-1457-z

Journal information: Nature
Provided by Washington University School of Medicine

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