The long lasting geographical and linguistic isolation, internal migrations, famines and rapid, recent expansions have moulded the population structure of Finland for thousands of years. Such population isolates provide exceptional opportunities for identification of genome variations underlying disease traits. When the unique population structure is combined with the one payer health care system, the harmonized training of physicians and tradition in epidemiological research Finland has become one the most interesting places for genetic epidemiology. The availability of large sample collections (www.nationalbiobanks.fi) has stimulated large international collaborative projects such as the SISu project (Sequencing Initiative Suomi).
Diseases of specific interest in the Palotie group are migraine, schizophrenia, epilepsy and some cardiovascular traits. The wealth of multiple large study samples enables the group to use different study designs for genome variant identification and verification and for the estimation of the size of the effect contributed by the variants. These include large collaborative genome wide association (GWAs) and sequencing studies and studies that utilize family structures and extreme population bottlenecks to identify low frequency variant detection.
FinnGen study launched in Finland in the autumn of 2017 is a unique study that combines genome information with digital health care data. The FinnGen study is an unprecedented global research project representing one of the largest studies of this type. Project aims to improve human health through genetic research, and ultimately identify new therapeutic targets and diagnostics for treating numerous diseases. The collaborative nature of the project is exceptional compare to many ongoing studies, and all the partners are working closely together to ensure appropriate transparency, data security and ownership.
FinnGen brings together Finnish universities, hospitals and hospital districts, THL, biobanks, international pharmaceutical companies and, hopefully hundreds of thousands of Finns. Collaboration is the key to achieving breakthroughs in disease prevention, diagnosis, and treatment.
The group has over 20 years track record in migraine genetics. It builds on a long collaboration between Dr. Mikko Kallela and Dr. Maija Wessman and the very large collection of Finnish migraine families, currently consisting of more than 1 700 families with DNA from about 10 000 family members. Dr. Palotie is chairing the International Headache Genetics Consortium (IHGC) consisting of more than 30 groups around the world. IHGC is performing large genome wide association studies (GWAS) and has identified numerous genome loci associated to migraine. Current projects include sequencing and expanded GWA studies to uncover more of the genomic landscape underlying migraine susceptibility.
The schizophrenia project build largely on the founding work by Professor Jouko Lönnqvist and his colleagues who established the Finnish schizophrenia family collection and large population cohorts with rich phenotype data and the ability to link individuals to National Health Registers. We use the unique Finnish population structure and cutting edge sequencing and genotyping methods to identify low frequency and rare variants contributing to severe mental health risk. We recently identified a deletion of the TOP3B gene enriched in the North Eastern part of the Country to be associated to schizophrenia and cognitive impairment (Stoll et al 2013). We are also a part of the international Psychiatric Genetics Consortium and the UK10K project.
As part of the collaborative SISu project we study variants enriched in the Finnish population through the bottleneck effects and their potential consequences on medically relevant phenotypes. We combine sequence and genotype data from large population cohorts such as Finrisk, Helsinki Birth Cohort, Young Finns, The Twin Cohort, Northern Finnish Birth Cohorts and Health 2000 with National Health Register data. This facilitates a phenome mining design to evaluate the potential phenotype effect of individual variants, e.g. loss of function variants, without any prior knowledge of the genes. We recently completed a study of more than 80 loss of function variants enriched in the Finnish population in 36 000 population cohort samples and identified several medically relevant associations (Lim et al).
Most of the current population in the north-eastern part of Finland are descendants of small founder populations established in the 17th century. This has resulted in population isolate structures in the region and an enrichment of recessive diseases. These areas also have higher prevalence of schizophrenia and government compensation for cognitive disability. We therefore hypothesize that some recessive-acting variants enriched in this area might contribute to some forms of cognitive impairment. Furthermore, while the contribution of de novo variants in more severe forms of intellectual disability (ID) has been extensively studied, less is known about genetic architecture of mild ID.
In collaboration with Dr. Outi Kuismin (FIMM, University of Oulu, Oulu University Hospital) and Dr. Jukka Moilanen (University of Oulu, Oulu University Hospital) we are collecting a comprehensive sample of patients with an unknown cognitive impairment etiology residing in Northern Finland. The cohort represents an unselected population of ID patients, and therefore most of the patients have the most common, mild form of ID.
In the first phase of collection, we studied 422 ID patients using exome sequencing and DNA microarray genotyping (Kurki et al. 2019). We showed that rare damaging variants in known ID genes are observed significantly more often in severe than in mild ID patients. We also showed that a common variant polygenic risk significantly contributes to ID. Additionally, we identified a Finnish enriched homozygous variant in the CRADD ID-associated gene.
We are currently extending the NFID collection and as of January 2020 have collected approximately 3000 cases (~1400 cases and ~1600 family members) in approximately 1250 families. Currently we are particularly focusing on inherited variants in large multiplex families (families with three or more individuals with ID).
In collaboration with Dr. Marja-Riitta Taskinen, Dr. Nelson Freimer (UCLA), Dr. Samuli Ripatti and Dr. Sanni Söderlund, funded by the NIH (NHLBI) program “Life after Linkage”, we are aiming to understand the genetic variation contributing to familial dyslipidemias. The families were collected in the 1990s as part of the EU funded EUFAM project. In these families there is an increased incidence of cardiovascular events along with dyslipidemic phenotypes. We use extensive lipid phenotyping, metabolomics, whole genome and exome sequencing to improve our understanding of genetic variation contributing to the increased risk of cardiovascular events and lipid profiles.
The Finnish SUPER study on genetic mechanisms of psychotic disorders is a 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 in order to provide more accurate information for the development of new therapeutic interventions. In Finland the national study was carried out during the years 2016-2018. The Finnish SUPER study successfully collected over 10,400 genetic samples from psychosis patients. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, was leading the study in collaboration with the National Institute for Health and Welfare (THL). Five university hospital districts were involved in the sample collection.