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

Karri Kaivola; Matti Pirinen; Hannu Laaksovirta; Lilja Jansson; Osma Rautila; Jyrki Launes; Laura Hokkanen; Jari Lahti; Johan G Eriksson; Timo E Strandberg; FinnGen; Pentti J Tienari

doi:10.3389/fgene.2023.1087098

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

Front Genet. 2023 Mar 1:14:1087098. doi: 10.3389/fgene.2023.1087098. eCollection 2023.

Authors

Karri Kaivola^{1

2}, Matti Pirinen^{3

4

5}, Hannu Laaksovirta², Lilja Jansson^{1

2}, Osma Rautila^{1

2}, Jyrki Launes⁶, Laura Hokkanen⁶, Jari Lahti⁶, Johan G Eriksson^{7

8

9

10}, Timo E Strandberg^{11

12}, FinnGen^{1

2

3

4

5

6

7

8

9

10

11

12}, Pentti J Tienari^{1

2}

Affiliations

¹ Translational Immunology, Research Programs Unit, University of Helsinki, Helsinki, Finland.
² Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
³ Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
⁴ Department of Public Health, University of Helsinki, Helsinki, Finland.
⁵ Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
⁶ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
⁷ Folkhälsan Research Center, Helsinki, Finland.
⁸ Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore, Singapore.
⁹ Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹⁰ Department of General Practice and Primary Healthcare, University of Helsinki, Helsinki, Finland.
¹¹ University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹² University of Oulu, Center for Life Course Health Research, Oulu, Finland.

Abstract

C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10^-307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10^-114) as well as alleles with ≥20 repeats. rs139185008*C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707*T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707*T and rs139185008*C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008*C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50-80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008*C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its' association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia.

Keywords: ALS; C9orf72; biobank; case-control analysis; intermediate allele; survival.

Grants and funding

This study was funded by the Finnish Cultural Foundation, Päivikki and Sakari Sohlberg Foundation, Paulo Foundation, The Finnish Brain Foundation, the Sigrid Juselius Foundation, Helsinki University Hospital grants, ALS tuttu ry and the Finnish Academy (318868).