July 23, 2019 | By Kari Oakes | MDedge

Having a first-degree relative with amyotrophic lateral sclerosis (ALS) increases the lifetime risk of developing the condition, even in the absence of a known ALS-associated genetic mutation, according to a recent Irish population–based study.

Among first-degree relatives of individuals with ALS whose genetic status was unknown, the lifetime risk of developing ALS was 1.4%, compared with 0.3% in the general population (P less than .001).

Overall, lifetime heritability for the 1,117 patients in the heritability study cohort was 52.3% (95% confidence interval, 42.9%-61.7%). The highest heritability was seen in mother-daughter dyads; here, the concordance rate for ALS was 2.6% and the heritability estimate was 66.2% (95% CI, 58.5%-73.9%), “pointing to a previously unrecognized sex-mediated association with disease heritability,” Marie Ryan, MD, and coauthors at Trinity College Dublin wrote in JAMA Neurology.

For the purposes of this study, heritability was defined as “the proportion of variance in liability that is attributable to additive genetic factors,” explained the investigators. Their model was applied to 1,123 Irish patients with incident ALS over a 10-year study period, drawing on a national database. Complete medical histories were available for both parents of every individual in the cohort, and the investigators identified 32 parent-offspring dyads with ALS.

In their assessment of “liability” for ALS, Dr. Ryan and colleagues accounted for age-specific and sex-specific ALS incidence rates, using a well-delineated United States reference population. They also took into account competing mortality risks that might intervene before an individual developed ALS.

Although mother-daughter dyads yielded the highest heritability estimates, heritability was also elevated among father-son dyads, at 50.1% (95% CI, 42.0%-59.4%). Opposite-sex dyads (mother-son and father-daughter) yielded similar, and lower, heritability estimates of 34%-38%. Dr. Ryan and coinvestigators acknowledged that female sex hormones might play a role in mediating risk for ALS, but the contribution and mechanism are currently unknown.

The investigators identified 674 patients in the cohort who had been tested for C9orf72; large repeat expansions in the GGGGCC segment of this gene are known to cause ALS. In all, 69 patients were C9orf72 positive, and 14 of these individuals (20.3%) reported that one parent had ALS. Among the entire cohort, 23 of the 32 patients with parents who also had ALS had C9orf72 testing, and 14 of 23 (60.9%) were positive. This discrepancy, wrote Dr. Ryan and coauthors, suggests that “genetic anticipation or pleiotropic effects may have masked the clinical phenotype in their parents.”

Parents were a mean 69.6 years old at the time of diagnosis, and offspring were a mean 52.0 years old; 56% of patients in the study cohort were male.

“[I]n our study, ALS heritability was assessed for the first time in a population in whom genetic mutations have been excluded,” wrote Dr. Ryan and coinvestigators. “We have found that, in the absence of known ALS-associated genetic mutations in the proband, first-degree relatives of individuals with ALS remain at increased risk of developing ALS compared with the general population.”

Dr. Ryan and one coauthor reported receiving funding from Science Foundation Ireland, and one coauthor reported receiving book royalties from Taylor & Francis, and fees from Cytokinetics and Wave Pharmaceuticals. The study was funded by Science Foundation Ireland and the Motor Neurone Disease Association.