Rare genetic variants are not the main cause of common diseases


Although some rare variants can significantly increase the risk of disease for a few individuals, the majority of the genetic contribution to common diseases is due to a combination of many common genetic variants with small effects. This is shown by researchers at IGP and other departments at Uppsala University in a new comprehensive study published in the journal Nature Communications.

It is known that genetic factors, together with lifestyle and environment, contribute to each individual's vulnerability to common non-communicable diseases, such as cardiovascular disease, inflammatory diseases and cancer. Over the past 15 years, researchers in genetic epidemiology have successfully identified genes that contribute to heredity, that is, the degree to which a given trait is inherited from parents to offspring via our genes. However, a significant part of the heritability has not yet been explained by the identified genetic variants. Until recently, technologies for genetic analysis have been limited to a selection of positions in our genome that are informative in most populations in the world.

In recent years, new DNA sequencing technologies, which enable researchers to study each individual position in the human genome in large cohorts, have become available. It has been shown that a large majority of the genetic variants in a cohort are very rare, and sometimes even specific to a particular country, or part of a country. It is therefore likely that previous genetic studies have disregarded a majority of the disease-causing genetic effects.

In the present study, the researchers used whole genome sequencing to characterise the genetic variation in a Swedish cohort of over 1000 participants and linked the genetic variation to functional consequences that are mediated via our proteins, the end product encoded by the genes.

“Proteins, the products of our genes, mediate the effects of our genes on the risk of disease. Characterising the relationship between variation at the genetic level and protein level is therefore of great importance for us to understand how genetic variation causes diseases, says Åsa Johansson at IGP, who led the study.

The researchers examined over four hundred proteins and showed that many of them were affected by genetic variation. It was obvious that the rare mutations often have greater effects on the proteins, compared to common variants. Rare varieties, however, do not seem to explain much of the heredity precisely because they are so rare. The results were also supported by theoretical calculations and challenge some of the hypotheses that have existed in the field for some time.

“Surprisingly, even though we use statistical models that have been developed to capture the effects of rare variants, we saw very few associations for the rare variants, in contrast to more common variants,” says Marcin Kierczak at the Department of Cell and Molecular Biology and bioinformatics expert at the NBIS infrastructure at SciLifeLab, who implemented the bioinformatics pipeline used in the analyses.

This suggests that the major component of the heredity of proteins, as well as of the common diseases that occur in response to the changes in our proteins, is much more due to common genetic variation and not the rare ones. But heredity is a measure of the total burden of genetic contribution to a disease in the population and the effect of rare variants at the individual level can still be high.

“Although our results showed that the major hereditary cause of our common diseases in the population is due to common variants, there is still a smaller proportion of individuals who carry rare variants that dramatically increase their disease risk,” says Åsa Johansson.

“It is therefore important to also emphasize the importance of using whole genome sequencing to find those individuals with a pronounced genetic risk of a common disease because these people are more suitable for future precision medicine therapy, says Valeria Lo Faro,” research assistant in Åsa Johansson’s group.

More information:
Article in Nature Communications
Research in Åsa Johansson’s group

Last modified: 2022-01-26