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

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.

Incidence of Syndromes Associated With Frontotemporal Lobar Degeneration in 9 European Countries

“…As recently demonstrated, the high rate found in Northern Savo may be linked to the prevalence of C9orf72 sequence variations specifically found in this area, as compared with other Finnish areas (ie, Northern Ostrobothnia). 30 Conversely, the low incidence detected in the Netherlands and in Stockholm might be due to incomplete ascertainment and nonuniform assessments in place across registries, which could also influence bias toward specific phenotypes. This interpretation needs to be confirmed in future prospective studies.…”

“…Indeed, from a geographical point of view, estimated FTLD incidence captured a relative homogeneity among different countries, with the exception of 1 district surveyed in Finland (Northern Savo) with the highest incidence rate and comparatively low incidence rates found in the Netherlands and Sweden. As recently demonstrated, the high rate found in Northern Savo may be linked to the prevalence of C9orf72 sequence variations specifically found in this area, as compared with other Finnish areas (ie, Northern Ostrobothnia) . Conversely, the low incidence detected in the Netherlands and in Stockholm might be due to incomplete ascertainment and nonuniform assessments in place across registries, which could also influence bias toward specific phenotypes.…”

C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity

“…The HRE-containing haplotypes seem to differ among European populations. It was previously shown that rs139185008 was not among the top SNPs associated with ALS in the UK Biobank (Rostalski et al, 2021). Here, we tested SNPs identified as HREtagging SNPs in a cohort from the Netherlands and United Kingdom.…”

“…Rs139185008 has been previously reported as the top HRE tagging SNP in Finland and associated with idiopathic normal pressure hydrocephalus as well as with FTD (3 × 10 −15 , OR 4.38) and ALS (3 × 10 −21 , OR 5.19) in the FinnGen release 5 (Korhonen et al, 2019;Rostalski et al, 2021).…”

Response to the letter by de Boer et al. (2022)

“…This risk may be conferred by the IAs as such, other variation on the haplotype or their combination. Haplotype heterogeneity regarding the best expansion-tagging SNPs has already been reported between Finnish and UK populations [ 10 ] and the above-mentioned differences in the frequencies of the 17–19 and ≥ 20 repeat alleles may reflect differences in the haplotype background of these alleles.…”