Modules of genotypic variance reflect heterogeneity across TDP‐43 proteinopathies

Abstract

AbstractBackgroundTAR DNA‐binding protein (TDP‐43) proteinopathies yield a variety of neurodegenerative conditions including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and hippocampal sclerosis of aging (HS‐Aging). However, the contribution of both shared and disparate single nucleotide polymorphisms (SNPs) to phenotypic presentations is unclear. We hypothesize that shared genetic variation may drive susceptibility across diseases while disparate genetic variation may contribute to our understanding of disease‐specific drivers.MethodWe compared the relative associations of GWAS summary statistics for ALS, FTLD‐TDP, and HS‐Aging using weighted correlation analysis to identify data‐driven modules of highly correlated SNPs. A gene ontology enrichment analysis for biological processes was performed separately for each identified module. Enrichment was determined by overrepresentation test. Module SNPs were used to construct polygenic risk scores (PRS). PRS were tested for association with neuropathological diagnosis in an independent sample of autopsy‐confirmed individuals.ResultWe identified 493,591 SNPs commonly genotyped across ALS, FTLD‐TDP, and HS‐Aging GWAS summary statistics, and the top 1% of these were selected for analysis. We identified five modules: three modules associated with a single GWAS phenotype, ALS (M1, containing 1,907 SNPs), FTLD‐TDP (M2, containing 1,727 SNPs), and HS‐Aging (M3, containing 1,031 SNPs), as well as two modules associated with the phenotypic pairs, ALS‐FTLD (M4, 140 SNPs) and FTLD‐HS (M5, containing 129 SNPs). The top 10 overrepresented pathways by fold enrichment that met FDR p<.05 include processes related to nervous system development, including neuron projection and axon guidance, and the regulation of synapse organization and assembly in M1‐ALS and M2‐FTLD‐TDP. Notably, M1‐ALS uniquely includes pathways involved in skeletal muscle satellite cell activation as well as metabolic processes, which have known dysfunction in ALS. Pathways related to neurogenesis were uniquely observed in M3‐HS‐Aging. A PRS was calculated for M1‐ALS and we observed a significantly higher dosage of risk in a neuropathologically‐defined sample of primary ALS (n=131) than primary FTLD‐TDP cases (n=110; d=.27, p=.04).ConclusionExamining genotypes revealed modules of both shared and disparate correlated SNPs across phenotypes associated with TDP‐43 proteinopathies which have biologically plausible pathway and neuropathological associations. We suggest that genetic variation across TDP‐43 proteinopathies may contribute to individual‐level presentations of these syndromes.