Inherited and noninherited genetic factors contribute equally to the risk for developing amyotrophic lateral sclerosis (ALS), and first-degree relatives of people with ALS tend to have a higher risk for disease compared with the general population, even in the absence of known ALS-associated genetic mutations. These findings are according to a study published in JAMA Neurology.

Incident cases of ALS recorded in the Irish ALS register between 1995 and 2017 were included in the study (n=1117). Based on these data, researchers calculated the annual age- and sex-specific standardized ALS incidence rates, averaged for 5 census years. Mortality-adjusted lifetime risk was also determined. Researchers also calculated the sex-specific heritability estimates for all cases in this cohort, as well as for patients who were known carriers of the C9orf72 (OMIM 614260) variant and for those with no known genetic risk.

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The researchers identified 32 parent-child ALS dyads, with 21.9% of these having received a diagnosis of cognitive-onset ALS. In 9 cases, affected offspring were younger at disease onset (mean age, 52.0 years; 95% CI, 48.8-55.3 years) vs their parents (mean age, 69.6 years; 95% CI, 62.4-76.9 years; P =.008). The lifetime risk for ALS in first-degree relatives of people with an ALS diagnosis was higher compared with the general population (1.4% vs 0.3%, respectively; P <.001).

Additionally, mean overall lifetime heritability of ALS was 52.3% (95% CI, 42.9%-61.7%) vs 36.9% (95% CI, 19.8%-53.9%) for individuals with no genetic risk. Mother-daughter pairings had the highest heritability estimates (66.2%; 95% CI, 58.5%-73.9%). A total of 69 patients diagnosed with ALS between 2008 and 2017 were C9orf72 positive, and 20.3% of these patients had a parental history of ALS. Up to 44.4% of patients whose fathers had ALS carried the C9orf72 repeat expansion, as did 71.4% of patients whose mothers had ALS.

Limitations of the study included the lack of assessment for environmental variables and their impact on ALS risk in this population. Further, despite accounting for known genes of large effect in the population studied, researchers were unable to control for unknown genes of large effect.

As it pertains to risk for developing ALS, genetics contributes to half of the overall variance, the researchers concluded. They believe that “even in a population devoid of known gene mutations, ALS heritability remains high, supporting ongoing efforts to identify causative genes.”

Disclosure: A study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Ryan M, Heverin M, McLaughlin RL, Hardiman O. Lifetime risk and heritability of amyotrophic lateral sclerosis [published online July 22, 2019]. JAMA Neurol. doi:10.1001/jamaneurol.2019.2044