The additive effect of genetic modifiers on ALS prognosis: a population-based study

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Abstract Objective To determine if the co-presence of genetic polymorphisms related to ALS has additive effects on the course of the disease in a population-based cohort of Italian patients. Methods The study population includes 1245 ALS patients identified through the Piemonte Register for ALS, diagnosed between 2007 and 2016 and not carrying SOD1, TARDBP and FUS mutations. Controls were 766 age, sex, and geographically matched Italian subjects. We considered UNC13A ( rs12608932), CAMTA1 ( rs2412208), SLC112A ( rs407135) and ZNF512B (ZNF512B) polymorphisms, as well as ATXN2 polyQ intermediate repeats and C9ORF72 GGGGCC intronic expansion. Results The variants in C9orf72 (p=0.016), ATXN2 (p<0.001) and UNC13A (p<0.001) were significantly related to survival in univariate analysis, while the other considered variants did not influence ALS outcome. However, in the Cox multivariable analysis, also CAMTA1 emerged to be independently related to survival. When assessing the interaction by pairs of genes, we found that the presence of both detrimental alleles/expansion was correlated with significantly shorter survival compared to subjects non-carrying both detrimental alleles/expansions. Each association of pairs of detrimental alleles was characterized by specific clinical phenotypes. Conclusions we demonstrated that gene polymorphisms acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental common polymorphism or repeat expansion, highlighting the clinical impact of our findings. In addition, the identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity and should be considered in designing and interpreting clinical trials. Key messages What is already known on this topic Besides the disease-causing genes, several other genes have been reported to act as modifiers of ALS phenotype, especially patients’ survival. However, the interactions of these genes at clinical level have never been explored. What this study adds We demonstrated that gene polymorphisms and expansions acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental allele at common polymorphism or repeat expansion, highlighting the clinical impact of our findings. How this study might affect research, practice, or polic The identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity, will have deep effects on clinical trial design and interpretation and support the inclusion of these polymorphisms in ALS genetic panels.

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