Sex-Specific Genetic Architecture of ALS: Evidence of a Female Protective Effect?

Abstract

Background: Amyotrophic lateral sclerosis (ALS) shows sex differences in incidence and age of onset, yet the underlying biological mechanisms remain poorly understood. Methods: We investigated sex-specific genetic architecture in an Italian ALS cohort with whole-genome sequencing (1,333 ALS cases, 755 controls). We performed a sex-stratified burden analysis of rare variants in ALS-associated genes and compared the proportions of male and female ALS patients carrying pathogenic or rare damaging variants. Key findings were replicated in the AnswerALS cohort (n = 723). Gene-specific sex ratios and familial history for C9ORF72, SOD1, and TARDBP were examined in an expanded dataset of 2,301 Italian ALS patients. Results: Sex-stratified burden testing revealed that rare variants in ALS genes were enriched in female cases versus controls (odds ratio [OR] 5.47, 95% confidence interval [CI] 1.60–34.29) but not in male cases. Female ALS patients more frequently carried rare damaging variants compared to males (23.2% vs 18.3%; OR 1.38, 95% CI 1.05–1.81), a finding that was replicated in the AnswerALS cohort (18.9% vs 12.4%; OR 1.58, 95% CI 1.10–2.26). Gene-level analyses of TARDBP carriers revealed a male predominance (2.1:1), yet a higher rate of familial history among females (40.4% vs 24.5%; OR 2.13, 95% CI 1.03–4.39). Interpretation: Females with ALS exhibited a higher overall burden of rare damaging variants, suggesting sex-related differences in genetic liability. Gene-level analyses indicate that the influence of sex varies across ALS genes, particularly TARDBP. These findings help explain epidemiological patterns and have implications for the identification of sex-linked protective mechanisms. ANN NEUROL 2026;99:1536–1544.