Neurodegenerative disease in C9orf72 repeat expansion carriers: population risk and effect of UNC13A

Abstract

The C9orf72 hexanucleotide repeat expansion (HRE) is the most common monogenetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neurodegenerative disease incidence in C9orf72 HRE carriers has been studied using cohorts from disease-affected families or by extrapolating from population disease incidence, potentially introducing bias. Age-specific cumulative incidence of ALS and dementia was estimated using Kaplan-Meier and competing risk models in C9orf72 HRE carriers compared to matched controls in UK Biobank. Risk modification by UNC13A genotype was examined. Of 490 331 individuals with valid genetic data, 701 had >100 repeats in C9orf72 [median age 55 (interquartile range 48-62), follow-up 13.4 years (12.3-14.1)]. The cumulative incidence of ALS or dementia was 66% (95% confidence interval 57%-73%) by age 80 in C9orf72 HRE carriers versus 5.8% (4.5%-7.0%) in controls, or 58% (50%-64%) versus 5.1% (4.1%-6.4%), accounting for the competing risk of other-cause mortality. Forty-one per cent of dementia incidence accrued between age 75-80. C-allele homozygosity at rs12608932 in UNC13A increased ALS or dementia risk in C9orf72 HRE carriers [hazard ratio 1.81 (1.18-2.78)]. C9orf72 HRE disease was incompletely penetrant in this population-based cohort, with risk modified by UNC13A genotype. This has implications for counselling at-risk individuals and modelling expected phenoconversion for prevention trials.

Keywords: C9orf72; UNC13A; amyotrophic lateral sclerosis; frontotemporal dementia; neurodegeneration.

Figure 1

Age-specific cumulative incidences of ALS and dementias in C9orf72 HRE carriers compared to matched controls. Kaplan–Meier plots of cumulative incidences of ALS, FTD, dementia and a combined outcome of ALS and dementia by age in individuals carrying the C9orf72 HRE (purple, n = 693) compared to age, sex, Townsend deprivation index and ethnicity-matched controls (green, n = 6930). Shaded bands indicate 95% confidence intervals. P-values were calculated by the log-rank test. Tables below represent the number of individuals at risk at a given time point (No C9 = No expansion; C9 = C9orf72 HRE expansion). Dementia refers to any-cause dementia (including FTD). ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; HRE = hexanucleotide repeat expansion.

Figure 2

C9orf72 expansion size and phenotype. (A) Association between C9orf72 expansion size and age at first recorded ALS or FTD diagnosis (n = 91). Points are coloured by diagnosis. (B) Association between C9orf72 expansion size and age of death in individuals with a recorded ALS or FTD diagnosis who have died. Points are coloured by diagnosis (n = 81). (C) Association between age at genetic testing and expansion size in individuals carrying a C9orf72 HRE (n = 701) (D) Expansion size and diagnosis (n = 74 for ALS, 26 for FTD, 8 for PD, 121 for any-cause dementia, 521 for No Dx). ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; HRE = hexanucleotide repeat expansion; No Dx = no neurodegenerative diagnosis recorded; PD = parkinsonism. Labels represent fitted linear regression models and associated P-values.

Figure 3

UNC13A genotype and neurodegenerative disease incidence. Kaplan–Meier plots of cumulative incidences of ALS, FTD, dementia and a combined outcome of ALS and dementia by age in individuals stratified by rs12608932 genotype, in the whole UK biobank cohort (top, n = 485 114) and in individuals carrying the C9orf72 HRE (bottom, n = 690). Shaded bands indicate 95% confidence intervals. P-values were calculated by the log-rank test. Tables below represent the number of individuals at risk at a given time point. ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; HRE = hexanucleotide repeat expansion.