Achievements of the Human genomics programme at FIMM

Novel genes and gene loci that underlie common diseases

In recent years, FIMM researchers have importantly contributed to discoveries of novel genes and gene loci that underlie common diseases with tens of publications in top medical journals, such as Science, Nature, Nature Genetics, and the Lancet. Research director Aarno Palotie has led the largest international consortium to study the genetics of migraine, which published, in 2016, the largest migraine GWAS combining data from over 20 groups worldwide. It pushes the identified migraine susceptibility loci over 40. The identified loci support the hypothesis that migraine susceptibility genes act on both vascular and neural tissues.

FIMM researchers have also led and contributed to projects leading to the discovery and characterisation of the effects of tens of genetic loci that modify circulating lipid levels, as well as more detailed lipoprotein fraction and serum metabolite levels. For many of the identified lipid loci, we have shown both the complex genetic architecture and their complex effects on metabolic fingerprints. This work has resulted in a series of publications led by our group and published in the highest scientific forums, such as Nature Genetics (Kettunen et al. 2012, Willer et al. 2013, CARDIoGRAMplusC4D 2013, Surakka et al. 2015, Gormley et al. 2016), PLoS Medicine (Würtz et al. 2014, Fall et al. 2013), PLOS Genetics (Ripatti et al. 2016, Tukiainen et al. 2014, Lim et al. 2014, Service et al. 2014), Bioinformatics (Pirinen et al. 2017), and the American Journal of Human Genetics (Benner et al. 2017).

Finnish disease heritage revisited

New exome-sequencing technology has allowed the concept of Finnish disease heritage to be revisited, and our researchers have identified new founder mutations enriched in Finland. In one study, the largest worldwide cohort of progressive myoclonus epilepsy was studied and used to identify a recurrent de novo mutation in KCNC1, demonstrating that the disease phenotype is very mutation specific and that it can occur repeatedly in the same nucleotide. FIMM researchers led by Janna Saarela have also discovered the responsible genes and mutations underlying a number of cases of immunodeficiency, and researchers in the Pirinen, Ripatti, and Daly groups have provided interesting new information about the fine-scale genetic structure in Finland that will inform future gene discovery efforts.

Building large-scale genetics resources

An important element of FIMM activities is in the collection and construction of large-scale genetics resources that help drive the field of human genetics forward globally and create diverse opportunities for research and clinical translation in our local community. Legacy cohorts collected over the past 30-40 years, such as the THL Finrisk cohort and the Finnish Twins collected by Academy Professor Kaprio have yielded numerous important insights to public health and human genetics, included in countless publications. These studies take advantage of unique opportunities that exist in Finland regarding registry health data and population genetics history, but without ground investments, the promise of this data is not realised. Thus, at FIMM we continue to invest in the development of critical resources in a number of medical genetics areas.

Among noteworthy new collections are the following

• The Finnish SUPER study on genetic mechanisms of psychotic disorders is part of the international Stanley Global Neuropsychiatric Genomics Initiative. The objective of the study is to better understand the genetic and biological background of psychotic disorders so to provide more accurate information for the development of new therapeutics. Finland was the European pilot country and we reached the target of collecting > 10,000 genetic samples from Finnish psychosis patients during 2016 - 2019. FIMM is leading the study in collaboration with THL.

• The FinnGen Project led by Research Director Palotie is an unprecedented public-private partnership launched in 2017 which aims to recruit and genotype individuals through all biobanks in Finland to study a total of at least 500,000 Finns. The data resource, combining the use of state-of-the-art genotyping with comprehensive registry endpoints and medical data, in conjunction with progressive national biobank legislation, will place Finland at the forefront of global efforts to improve health through genetics and data mining.

• The GeneRISK Project led by Professor Ripatti and Group Leader Widén tests the behavioral and health effects of returning genomic and traditional risk-factor-based cardiovascular risk predictions back to participants. In GeneRISK, 7,350 individuals collected from Carea, Mehiläinen, and Red Cross Blood Service have been tested for known traditional and genomic risk factors and include an 18-month clinical follow-up that is currently on-going. In addition to providing crucial information on effects of implementing genomic preventive actions in routine health check-ups, the GeneRISK Study works as a biobanked longitudinal data resource for future studies.

Centre of Excellence in Complex Disease Genetics

Revealing the molecular mechanisms underlying common complex diseases holds the promise of improved and targeted prediction, prevention, diagnosis, and treatment. Building on unique resources and an extensive track record in disease genetic studies in Finland, in 2017 we proposed, and were awarded, a Centre of Excellence in Complex Disease Genetics to develop and apply a powerful, reliable, and general strategy for comprehensive identification of risk and protective variants. In particular, we sought to target novel high-impact low-frequency alleles that contribute significantly to common diseases, and to develop test and implementation strategies for genomic precision medicine.