A Novel Genetic Marker for the C9orf72 Repeat Expansion in the Finnish Population

Article type: Research Article

Authors: Rostalski, Hannah^a | Korhonen, Ville^b | Kuulasmaa, Teemu^c | Solje, Eino^{d; e} | Krüger, Johanna^{f; g} | Gen, Finn^h | Kaivola, Karri^h | Eide, Per Kristianⁱ | Lambert, Jean-Charles^j | Julkunen, Valtteri^{d; e} | Tienari, Pentti J.^h | Remes, Anne M.^{f; g} | Leinonen, Ville^b | Hiltunen, Mikko^{c; *; 1} | Haapasalo, Annakaisa^{a; *; 1}

Affiliations: [a] A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland | [b] Neurocenter, Neurosurgery, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland | [c] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland | [d] Institute of Clinical Medicine - Neurology, University of Eastern Finland | [e] Neuro Center, Neurology, Kuopio University Hospital, Kuopio, Finland | [f] Research Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland | [g] Medical Research Center (MRC), Oulu University Hospital, Oulu, Finland | [h] Department of Neurology, Helsinki University Hospital and Translational Immunology Program, Biomedicum, University of Helsinki, Helsinki, Finland | [i] Oslo University Hospital-Rikshospitalet; and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway | [j] Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liés au vieillissement, Lille, France

Correspondence: [*] Correspondence to: Annakaisa Haapasalo, PhD, Adjunct Professor, Research Director, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P. O. Box 1627 (Neulaniementie 2), 70211 Kuopio, Finland. Tel.: +358403552768; E-mail: annakaisa.haapasalo@uef.fi and Mikko Hiltunen, PhD, Professor, Institute of Biomedicine, Yliopistonranta 1E, University of Eastern Finland, 70211 Kuopio, Finland. Tel.: +358403552014; E-mail: mikko.hiltunen@uef.fi.

Note: [1] These authors contributed equally to this work.

Abstract: Background:C9orf72 repeat expansion (C9exp) is the most common genetic cause underlying frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, detection of the C9exp requires elaborative methods. Objective:Identification of C9exp carriers from genotyped cohorts could be facilitated by using single nucleotide polymorphisms (SNPs) as markers for the C9exp. Methods:We elucidated the potential of the previously described Finnish risk haplotype, defined by the SNP rs3849942, to identify potential C9exp carriers among 218,792 Finns using the FinnGen database. The haplotype approach was first tested in an idiopathic normal pressure hydrocephalus (iNPH) patient cohort (European Alzheimer’s Disease DNA BioBank) containing C9exp carriers by comparing intermediate (15–30) and full-length (> 60 repeats) C9exp carriers (n = 41) to C9exp negative patients (< 15 repeats, n = 801). Results:In this analysis, rs3849942 was associated with carriership of C9exp (OR 8.44, p < 2×10–15), while the strongest association was found with rs139185008 (OR 39.4, p < 5×10–18). Unbiased analysis of rs139185008 in FinnGen showed the strongest association with FTLD (OR 4.38, 3×10–15) and motor neuron disease ALS (OR 5.19, 3×10–21). rs139185008 was the top SNP in all diseases (iNPH, FTLD, ALS), and further showed a strong association with ALS in the UK Biobank (p = 9.0×10–8). Conclusion:Our findings suggest that rs139185008 is a useful marker to identify potential C9exp carriers in the genotyped cohorts and biobanks originating from Finland.

Keywords: Amyotrophic lateral sclerosis, C9orf72, DNA repeat expansion, frontotemporal lobar degeneration, motor neuron disease, polymorphism, single nucleotide

DOI: 10.3233/JAD-210599

Journal: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1325-1332, 2021