A new study led by researchers at the University of Eastern Finland in collaboration with FinnGen and international partners provides a novel genetic tool to identify C9orf72 repeat expansion-carrying frontotemporal lobar degeneration or ALS patients from large population-based cohorts.

Identifying a Novel Genetic Marker

Hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of both frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). It is exceptionally prevalent among Finnish FTLD and ALS patients. The detection of the C9orf72repeat expansion requires specific genetic analyses, which are laborious and not applicable for large population-based sample sets.

In the new study, researchers utilized novel genetic single nucleotide polymorphisms (SNPs) associating with the C9orf72 expansion to identify potential expansion carriers from large, genotyped patient cohorts in Europe and Finland. The study was published in the Journal of Alzheimer’s Disease.

Using the genetic information of patients carrying and not carrying the C9orf72 expansion available in the large European EADB cohort (A European DNA bank for deciphering the missing heritability of Alzheimer’s disease), researchers  first identified SNP markers that separated C9orf72 expansion carriers from non-carriers. Previous studies have described a group of 20 SNPs, which associated with the C9orf72 repeat expansion in FTLD and ALS patients. However, instead of this group of SNPs, a previously unreported SNP, referred to as rs139185008, showed the highest specificity in the Finnish C9orf72 repeat expansion carriers.

Making an Connection with ALS and FTLD

Next, the researchers tested which disease groups this novel rs139185008 SNP associated with in the large population-based FinnGen database, which contains genetic information and medical records of approximately 300,000 Finns. FinnGen brings together Finnish universities, hospitals and hospital districts, the Finnish Institute for Health and Welfare (THL), the Finnish Red Cross Blood Service, biobanks and international pharmaceutical companies in order to collect and analyze genome and health data from 500,000 Finnish biobank participants. Using FinnGen information, rs139185008 showed the strongest association with patients having a clinical diagnosis of FTLD and motor neuron disease ALS. The SNP also strongly associated with ALS in the UK Biobank. These findings altogether suggest that this new SNP is a useful novel genetic surrogate marker for identifying C9orf72 repeat expansion carriers in large, genotyped population-based cohorts. 

Because the FinnGen database does not directly contain complex genetic information, such as that related to repeat expansions, the identified carriers of the SNP rs139185008 need to be further examined in the future using a specific genetic method to confirm that they indeed carry the C9orf72 repeat expansion. “This will help to evaluate the full potential of the rs139185008 as a novel genetic tool to identify C9orf72 repeat expansion carriers from large, population-based cohorts,” says Research Director Annakaisa Haapasalo from UEF’s A.I. Virtanen Institute for Molecular Sciences.

“This study might be the beginning of other future projects using the FinnGen database to explore genotype-phenotype associations among neurodegenerative diseases. Similar approach using specific SNPs as surrogate markers to detect repeat expansions may also prove useful in the case of other repeat expansion diseases,” says Professor Mikko Hiltunen from UEF’s Institute of Biomedicine.

The study was led by Hiltunen and Haapasalo in collaboration with Professor Ville Leinonen from the University of Eastern Finland, Professor Anne Remes from the University of Oulu, Professor Pentti Tienari from the University of Helsinki, Professor Per Kristian Eide from the University of Oslo, and Professor Jean-Charles Lambert from Institut Pasteur de Lille.

The main author of the article, MSc Hannah Rostalski is an Early-Stage Researcher in the GenomMed Doctoral Programme at UEF. Exploring the link between the C9orf72 repeat expansion and neurodegeneration is in the focus of her PhD project. The expertise of Research Manager Teemu Kuulasmaa from the UEF Bioinformatics Centre was essential in the bioinformatic analyses.

The study was supported by the Academy of Finland, UEF’s Strategic Neuroscience Funding, the Finnish Brain Foundation, Sigrid Jusélius Foundation, Instrumentarium Science Foundation, Orion Research Foundation, and ALtuttu ry. The work is also part of the research activities of the Finnish FTD Research Network (FinFTD). The publication is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 740264.