Beyond Mendel: FinnGen study sheds new light on well-established theories of genetic inheritance
A large-scale biobank-based study performed in Finland has discovered several new disease genes as well as new insights on how known genetic factors affect disease. The study highlights an underappreciated complexity in the dosage effects of genetic variants.
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 on January 18, 2023, 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 diseases that one only gets if one inherited a dysfunctional genetic variant from both parents (recessive inheritance).
“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”, explains Dr Henrike Heyne, first author of the study from the Institute for Molecular Medicine Finland FIMM, University of Helsinki (now group leader at HPI, Germany).
However, 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 Henrike 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 (protecting from heart arrhythmia or protecting from hypertension) 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”, says Heidi Rehm, an author on the paper and Professor of Pathology at Massachusetts General Hospital and Medical Director of the Broad Clinical Lab.
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. 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”, says Mark Daly, senior author on the paper and Director of the Institute for Molecular Medicine Finland (FIMM) and faculty member at Massachusetts General Hospital and the Broad Institute.
Original publication: Mono- and biallelic variant effects on disease at biobank scale. H. O. Heyne, J. Karjalainen, K. J. Karczewski, S. M. Lemmelä, W. Zhou, FinnGen, A. S. Havulinna, M. Kurki, H. L. Rehm, A. Palotie, M. J. Daly. Nature 2023, DOI: 10.1038/s41586-022-05420-7.
JOURNAL
Nature
SUBJECT OF RESEARCH
Cells
ARTICLE TITLE
Mono- and biallelic variant effects on disease at biobank scale
ARTICLE PUBLICATION DATE
18-Jan-2023
The power of a genetic isolate: Hundreds of novel genetic discoveries from the FinnGen study
New results from the FinnGen research consortium demonstrate the undeniable benefits of Finnish health research environment for genomic research. Among the wealth of novel genetic discoveries are previously unknown genetic risk factors for many debilitating diseases. These findings have potential to facilitate the development of new therapies.
Since initiation in 2017, the FinnGen study has developed into one of the world’s leading biobank-based genomic research projects. Currently FinnGen is completing the construction of a resource that integrates genomic information from 500,000 Finns with more than half a century of national health registry data.
The FinnGen flagship study, just published in Nature, is a convincing demonstration of the opportunities unique to Finnish health data, population structure, legislative frameworks and biobanking organization that in combination exist nowhere else.
Here the FinnGen team describes results based on 224,737 Finnish biobank participants. After performing comprehensive genetic analyses for more than 1,900 diseases, the researchers identify almost 2,500 genomic regions that are linked with at least one of these diseases.
“Even with less than half of the recruited 500,000 participants analyzed at this stage, this snapshot of results describes a wealth of important genetic discoveries emerging from FinnGen, including novel risk and protective variants for both common and rare diseases”, says FinnGen Scientific Director, Professor Aarno Palotie from the Institute for Molecular Medicine Finland FIMM, University of Helsinki.
Finland’s health registers and biobanks provide unique opportunities
In Finland, health information such as medical diagnoses, procedures and drug prescriptions are captured for many decades in national electronic health registers for the entire population. This creates unique research opportunities.
In the flagship publication, the team first demonstrates that with skillful utilization of such register data, the health history of the study participants can be reliably composed and studied. For this, the authors compare the FinnGen results with earlier genetic findings for 15 previously well-studied common diseases, such as type 2 diabetes, asthma and Alzheimer’s disease.
In addition to verifying the validity of register data, the researchers show that identification of novel risk variants in FinnGen is possible with a much smaller number of patients compared to the largest published disease-specific genetic studies.
“The Finnish health registers containing health and medication data throughout an individual's lifetime, allowed us to rapidly and accurately identify disease cases. This accurate phenotyping, coupled with Finnish population history is a very powerful combination for novel genetic discoveries in a wide variety of diseases”, comments Dr. Mitja Kurki, the first author of the study from the Broad Institute of MIT and Harvard and the University of Helsinki.
New entry points into the disease biology
Finland’s unique geographic position and linguistic isolation are such that Finns have a distinct ancestry dating back to a small founding population approximately 100-150 generations. As a result, the modern Finnish population, despite being broadly similar to Europeans genetically, has an unusual and large set of genetic variants not often found elsewhere in the world. Several hundred of the 2,500 disease linked variants described in the study are in this category.
Among these variants, the researchers highlight 29 that are located in genes not previously linked to any disease. One example is a variant in a gene called TNRC18 that predisposes to inflammatory bowel disease and other inflammatory conditions. Other examples include variants increasing the risk of hypothyroidism, hearing loss or endometriosis, and variants that offer protection from arthrosis, glaucoma or heart disease.
“These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through variants that are rather rare, but have a strong biological impact”, says Mark Daly, the Director of the Institute for Molecular Medicine Finland FIMM at the University of Helsinki, the lead organization behind the study.
Additional FinnGen papers published this week provide fascinating examples of findings that increase our understanding of genetic predictors of medication use patterns as well as mechanisms leading to otosclerosis and respiratory infections, among other diseases. Furthermore, another FinnGen paper published in the same issue of Nature highlights that the classical inheritance models traditionally considered in genomic research and clinical diagnostics do not fully capture the range of genetic effects observed in populations.
One of the unique aspects of FinnGen is that in addition to public funding, FinnGen is supported by 13 pharmaceutical companies and has had shared scientific direction from academic and industry partners. The FinnGen study is thus ideally situated to address fundamental research questions with the potential to impact therapeutic development and delivery.
“With all this new information, the genetic composition of the Finnish population is now unquestionably among the best known in the world. However, the impact of our study is much broader and can benefit patients everywhere”, Professor Palotie emphasizes.
About FinnGen
The FinnGen study, launched in autumn 2017, is a broad academic-industrial collaboration between the Finnish biobanks and their respective universities and university hospitals, the Finnish Institute of Health and Welfare (THL), the Finnish Red Cross Blood Service, the Finnish Biobank Cooperative – FINBB and thirteen international pharmaceutical companies. The study is funded by Business Finland and the industrial partners AbbVie, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, a member of the Roche Group, GlaxoSmithKline (GSK), Janssen, Maze Therapeutics, MSD (the tradename of Merck Sharp & Dohme LLC), Novartis, Pfizer and Sanofi. University of Helsinki is the academic organization responsible for the study. As of November 2022, FinnGen has generated genotype and phenotype data from 429,221 biobank samples and is on track to complete the resource construction phase in 2023. The results of the study are publicly available (more information here). For accessing the individual-level biobank samples and data, please visit the Fingenious portal.
Additional information
Short FinnGen video: https://vimeo.com/789679108/943f573ff6
JOURNAL
Nature
ARTICLE TITLE
FinnGen provides genetic insights from a well-phenotyped isolated population
ARTICLE PUBLICATION DATE
18-Jan-2023
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