A novel genetic marker for the <em>C9orf72</em> repeat expansion in the Finnish population

Abstract

<div lang="en" class="abs"><p class="abs_header">Abstract</p><p><em>Background:</em> <em>C9orf72</em> repeat expansion (C9_exp) is the most common genetic cause underlying frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, detection of the C9_exprequires elaborative methods.</p><p><em>Objective:</em> Identification of C9_exp carriers from genotyped cohorts could be facilitated by using single nucleotide polymorphisms (SNPs) as markers for the C9_exp.</p><p><em>Methods:</em> We elucidated the potential of the previously described Finnish risk haplotype, defined by the SNP rs3849942, to identify potential C9_exp 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 C9_exp carriers by comparing intermediate (15–30) and full-length (> 60 repeats) C9_exp carriers (n = 41) to C9_exp negative patients (< 15 repeats, n = 801).</p><p><em>Results:</em> In this analysis, rs3849942 was associated with carriership of C9_exp (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).</p><p><em>Conclusions:</em> Our findings suggest that rs139185008 is a useful marker to identify potential C9_exp carriers in the genotyped cohorts and biobanks originating from Finland.</p></div>