FinnGen study highlights underappreciated complexity of dosage in genetic variation

An international team of scientists led by researchers at the University of Helsinki and the Broad Institute of MIT and Harvard examined the effects of 44,370 genetic variants on more than 2000 diseases in almost 177,000 Finnish biobank participants. The study focused on so-called coding genetic variants, i.e., variants that are known to change the protein product of the gene.

The results of the study, published in Nature, convey that the reality of genetic inheritance is more complex than the Mendelian inheritance laws taught in biology classes all around the world.

What is special about the study, apart from the size of the data set, is that the team  searched at scale specifically for recessive diseases – conditions that one only develops if one inherits a dysfunctional genetic variant from both parents.

"Researchers usually only search for additive effects when they try to find common genetic variants that influence disease risk. It is more challenging to identify recessively inherited effects on diseases as you need very large sample sizes to find the rare occasions where individuals have two dysfunctional variants," explained study first author Henrike Heyne of the Institute for Molecular Medicine Finland (FIMM) at the University of Helsinki, the Analytic and Translational Genetics Unit (ATGU) of Massachusetts General Hospital (MGH), and the Program in Medical and Population Genetics (MPG) at the Broad Institute. Heyne was co-corresponding author on the study with Mark Daly, director of FIMM at the University of Helsinki, founding chief of the MGH ATGU, and an institute member at Broad.

The extensive FinnGen study sample, collected from Finland, offers an ideal setting for such studies. The Finnish population has experienced several historical events that have led to a reduction of the population size and also been relatively isolated from other European populations. For this reason, a subset of dysfunctional and therefore potentially disease-causing genetic variants are present at higher frequencies, making the search for new rare disease associations of recessive inheritance easier.

Acknowledging this benefit, the researchers performed genome-wide association studies (GWAS) on 2,444 diseases derived from national healthcare registries, testing both additive and recessive inheritance models.

As a result, the team was able to detect known and novel recessive associations across a broad spectrum of traits such as retinal dystrophy, adult-onset cataract, hearing loss, and female infertility that would have been missed with the traditional additive model.

"Our study showed that the search for recessive effects in genome-wide association studies can be worthwhile, especially if somewhat rarer genetic variants are included, as is the case in the FinnGen study," says Heyne.

In addition, the dataset has provided a new perspective on the inheritance of known disease variants. For rare disease genes, inheritance is traditionally almost exclusively described as recessive or dominant. The study shows, however, that the reality is somewhat more diverse.

The researchers found, for example, that some variants that are known to cause genetic disease with recessive inheritance also have some attenuated effects when only one disease-causing variant is present, which other studies confirm. They also find genetic variants with beneficial effects (protective against heart arrhythmia or hypertension, for example) in genes that are associated with severe disease.

These results demonstrate that the so-called Mendelian laws based on the experiments with peas done in 1856, in a monastery garden near Brno (today Czech Republic) by the monk Gregor Mendel do not fully capture all aspects of inheritance of rare diseases.

“With the increased usage of carrier screening in the general population, whereby many individuals are learning that they are carriers for multiple pathogenic variants, understanding which of those variants may have mild health effects could be incredibly important for these individuals”, said paper author Heidi Rehm, an institute member in and co-director of the Broad MPG, a professor of pathology at MGH, and medical director of the Clinical Research Sequencing Platform at Broad.

The study could contribute to the integration of the traditionally separate but more and more overlapping scientific fields that study either the effect of rare genetic variants on rare disease or the effect of common genetic variants on common disease. The results demonstrate how large biobank studies, particularly in founder populations such as Finland, can broaden our understanding of the sometimes more complex dosage effects of genetic variants on disease.

“This study highlights the importance of integrating the large-scale biobank approach with detailed insights that emerge from rare disease studies," said study senior author Daly. "A more complete understanding of the role of genetic variation in each gene only emerges when we take account of all of the perspectives and insights from diverse study designs."

Adapted from a press release issued by FinnGen.