Modules of genotypic variance reflect heterogeneity across TDP-43 proteinopathies

Abstract

AbstractThe contribution of genotypes to the shared and disparate clinical and pathologic features observed across TDP-43 proteinopathies is unclear. TDP-43 pathology can contribute to very different neurodegenerative conditions, including frontotemporal lobar degeneration with TDP-43 (FTLD-TDP), amyotrophic lateral sclerosis (ALS), and hippocampal sclerosis of aging (HS-Aging). Despite mounting evidence for shared genetic risk across these TDP-43 proteinopathies, the drivers of individual-level presentations of these syndromes are unknown. We identified data-driven modules of correlated single nucleotide polymorphisms using GWAS summary statistics. These genomic features were either phenotype specific or shared across TDP-43 proteinopathy phenotypes and may contribute to phenotypic heterogeneity in these cases. Pathway analysis revealed biologically meaningful associations within the identified modules, including common nervous system processes and distinct, phenotype-specific associations. We derived module-specific polygenic scores and hypothesized that they would contribute to individual-level differences in the clinical presentation and corresponding anatomic distribution of pathology. Within characteristic FTLD-TDP brain regions, higher FTLD-TDP polygenic risk associated with higher TDP-43 burden. Further, module-specific ALS and FTLD-TDP polygenic risk associated with clinical phenotypic heterogeneity, even within the context of autosomal dominant mutation carriers. We suggest that genotypic variation across TDP-43 proteinopathies may contribute to individual-level presentations of these syndromes.