Determining the genetic background of diseases represents one of the great challenges for genetics research. The focus of research is on the interaction between the genome and the environment, and the unique data arising from studies of twins helps in analyzing this interaction. The genetic material of twins is suitable for gene mapping, the objective of which is to find statistical correlation between an individual’s genotype and phenotype.

The effect of the genome on disease etiology is a mystery that is slowly unfolding. The National Institute for Health and Welfare (NIHW, previously the National Public Health Institute) is studying genetic backgrounds of nationally significant diseases, and the increased knowledge on inheritance has provided a good boost for research. Despite the progress, only a fraction of the mechanisms behind the genetic history of diseases can be explained.

”So far we can only explain a few, at best, four to five percent of the total material,” says genetics researcher,
Adjunct Professor Markus Perola from the NIHW.

Adjunct Professor Markus Perola works to improve national health. The information about the genetic backgrounds of nationally significant diseases is currently insufficient, but genetics research is revealing the mystery of the human genome gene by gene. © Arto Wiikari

Perola considers that twin research provides a fruitful method of approaching genes, because by using identical twins it is possible to study the genome regions that make the twins’ phenotypes different from each other.

”With certain limitations, by studying identical twins we get two phenotypes at the price of one,” Perola concludes.

Over the period 2002 - 2006 the GenomEUtwin project collected research material for the genome-wide research. In this massive twin research project data was collected on 6000 pairs of twins, and Perola says that the project will continue generating further research on an ”ad infinitum” basis. The project focuses on the effect of the genome and the environmenton, for example, body height andweight, and susceptibility to migraine, coronary heart disease, and stroke.

One of the main results from the twin cohort project reveals information of adult stature: according to the results, the genome explains 80 percent of the observed variation in human height. The impact of an individual
gene is small, but the combined effect of several genes on adult height can cause a difference of several tens of centimeters.

Collaboration is esential

According to Perola, research collaboration between scientists was one of the concrete and most beneficial things about this international EU project.

”Through this project we have created a straightforward collaboration pattern, and I consider it indispensable. This is the first time we have collaborated on such a large scale and with such a high degree of coordination; those who previously competed against each other have now combined their materials.”

As for himself, Perola is interested especially in the results inflation and the search for weak variants across the whole genome.

”Though we create hundreds of thousands of markers across the genome, much of it still remains unresolved. We can only detect a few percent of the genomic variation and it is clear that we miss something. It is interesting to develop means that can be used to detect weak variants.”

Currently Perola’s group is analyzing genomic traits in blood lipids.

”Lipids can be shown to have a lot of genetic variation. They are heritable, clinically significant, and can be internationally standardized, which makes it easy to combine measurements carried out in several countries. Plenty of data was already available and in practice lipid analyses are easy and affordable to perform.”

"It seems probable that genes will be discovered that do not increase or decrease blood lipids alone but through interaction with other genes do increase blood cholesterol,” Perola explains.

Twin cohort data are being compared with national data that already exist, and this also increases the computation capacity required. According to Perola,the fast progress in genome-wide research is a triumph for engineering skills.

”As gene researchers, we have expressed our wishes as to what we need and how much we would be willing to pay for it. The rest has been a triumphal march of technology.”

More speed – more information

Genetic mapping is a complex and challenging task, shared by specialists in several different fields. Computer science researcher Tero Hiekkalinna has been responsible for developing research methods and comparing them.

Genomics research has developed in giant steps - thanks to engineering skills. Computer science researcher Tero Hiekkalinna acknowledges that time represents a challenge for processing research material. © Arto Wiikari

In the EUtwin project Hiekkalinna facilitated and speeded up the analysis and computation of the project results.

”The files are enormous and analyzing the material would need a huge amount of manual work and typing. I created and wrote the programs that automatically fetch information from thousands of files, which reduces the work of weeks to only a few days,” Hiekkalinna explains.

The current machinery provides huge possibilities, and the speed of computation is superb. Currently Hiekkalinna is preparing his doctoral dissertation on mathematical modeling of complex diseases, using family-based association mapping.

”The more complex family genomes get, the heavier the computation becomes. The challenge is to design our
method to be more powerful than the others: computational robustness and minimized consumption of time represent the challenge. The most critical element is speed,” Hiekkalinna emphasizes.

Genetics research increases our knowledge on the interaction of the genome and the environment, but we are far from direct clinical applications. According to Markus Perola, a large amount of genetic information exists, and the challenge for research is the intelligent analysis of this material.

”Diseases have to be understood as a whole. Research does not fight against genes but against diseases, and the major cause of obesity, for example, lies in what we eat, not in our genes. Risk management is really difficult; for example, since the 1960s the predispositions caused by tobacco have been widely known, yet 20 percent continue smoking. If it were suggested that the same amount of money as is invested in research were invested in preventive work, I would say why not. However, one has to be humble and realize that the treatment of risk factors is really difficult, and new information is needed also for educational purposes. Standing still must never be an alternative.”

”We are far from applications, but our goal is to increase understanding. The ultimate goal, of course, is to improve public health in Finland. This is not an empty statement; we keep it constantly in mind,” says Perola.

Mirkka Ruohonen

A genetic map of the genes affecting adult height. Genetic linkage analysis was used for locating genes affecting stature. This method utilizes genetic markers known to show variation between individuals. The markers are evenly distributed across the entire genome and they are determined from DNA samples. By using these markers it is possible to determine, by means of the linkage analysis, the chromosomal regions that are similar in family members showing a strong correlation in height. As a result, scientists can estimate the statistical probability of the region containing genes associated with adult stature. Statistical significance for the detected linkages must then be determined through computer simulation.
© Markus Perola

More information:

http://www.csc.fi/english/csc/news/news/height_research2008-2-22

http://www.genomeutwin.org/

Perola M, Sammalisto S, Hiekkalinna T, et all: GenomEUtwin Project. Combined genome scans for body stature in 6,602 European twins: evidence for common Caucasian loci. PL oS Genet.2007 Jun;3(6):e97. Epub 2007 May 2.