Heritability of ALS: A Population-based study over 24 years. (S54.001)

Objective: To determine the heritability of Amyotrophic Lateral Sclerosis (ALS). Background: Heritability describes the proportion of risk of developing a condition that is explained by genetic factors. ALS is known to be of complex genetic origin, but the heritability of the disease remains unclear. To resolve this question, we have conducted the largest population-based study of ALS heritability to date. Design/Methods: Using data from the Irish ALS register, between 2008 and 2017, we calculated 1) age-adjusted lifetime risks of developing ALS, 2) ALS concordance rates in parent-offspring pairs and 3) overall and sex-specific ALS heritability estimates. Results: 1117 Irish patients with ALS were included in the study. The lifetime risk of developing ALS in the Irish population is 2.88 and 2.29 per 1,000 men and women respectively, corresponding to 1 in 347 men and 1 in 436 women. The total lifetime risk of developing ALS is 1.43% in any first-degree relative of those with ALS. Overall, the heritability of ALS is between 40–50%, adjusted for the underlying age and sex structure of the population. Heritability estimates of over 70% were observed in female parent-offspring concordant pairs, a previously unrecognized sex-specific effect. Conclusions: Genetic factors account for close to 50% of the risk for developing ALS. Notwithstanding, while the risk of developing ALS in first-degree relatives of those affected is increased, in the absence of a known Mendelian inherited gene, the overall risk to relatives is low. However, genetic factors likely play a greater role in the development of the disease among female patients. Disclosure: Dr. Ryan has nothing to disclose. Dr. Heverin has nothing to disclose. Dr. Pender has nothing to disclose. Dr. McLaughlin has nothing to disclose. Dr. Hardiman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences, Cytokinetics, Treeway. Dr. Hardiman has received personal compensation in an editorial capacity for Taylor and Francis .