Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis

Abstract

Importance: Heritability describes the proportion of variance in the risk of developing a condition that is explained by genetic factors. Although amyotrophic lateral sclerosis (ALS) is known to have a complex genetic origin, disease heritability remains unclear.

Objectives: To determine the extent of ALS heritability and assess the association of sex with disease transmission.

Design, setting, and participants: A prospective population-based parent-offspring heritability study was conducted from January 1, 2008, to December 31, 2017 to assess ALS heritability, and was the first study to assess heritability in the context of known gene mutations of large effect. A total of 1123 incident cases of ALS, diagnosed according to the El Escorial criteria and recorded on the Irish ALS register, were identified. Ninety-two individuals were excluded (non-Irish parental origin [n = 86] and familial ALS [n = 6]), and 1117 patients were included in the final analysis.

Main outcomes and measures: Annual age-specific and sex-specific standardized ALS incidence and mortality-adjusted lifetime risk were determined. Sex-specific heritability estimates were calculated for the overall study cohort, for those known to carry the C9orf72 (OMIM 614260) variant, and for those with no known genetic risk.

Results: A total of 32 parent-child ALS dyads were identified during the study period. Affected offspring were younger at the onset of disease (mean age, 52.0 years; 95% CI, 48.8-55.3 years) compared with their parents (mean age, 69.6 years; 95% CI, 62.4-76.9 years; P = .008). Lifetime risk of developing ALS in first-degree relatives of individuals with ALS was increased compared with the general population (1.4% [32 of 2234] vs 0.3% [2.6 of 1000]; P < .001). Mean lifetime heritability of ALS for the overall study cohort was 52.3% (95% CI, 42.9%-61.7%) and 36.9% (95% CI, 19.8%-53.9%) for those with no known genetic risk. Heritability estimates were highest in mother-daughter pairings (66.2%; 95% CI, 58.5%-73.9%).

Conclusions and relevance: This population-based study confirms that up to 50% of variance in ALS has a genetic basis, and that the presence of the C9orf72 variant is an important determinant of heritability. First-degree relatives of individuals with ALS without a known genetic basis remain at increased risk of developing ALS compared with the general population. A higher heritability estimate in mother-daughter pairings points to a sex-mediated effect that has been previously unrecognized.

Figure.. Sex-Specific Heritability Estimates by Overall Heritability Cohort and C9orf72-Negative Subcohort

A, Mean heritability estimates for overall patient cohort, with lifetime risk of developing amyotrophic lateral sclerosis of 1.5 per 1000 males and 1.2 per 1000 females. B, Mean heritability estimates for C9orf72-negative patient subcohort, with lifetime risk of developing amyotrophic lateral sclerosis of 1.5 per 1000 males and 1.2 per 1000 females. Vertical lines indicate 95% CIs.