Genetic Contributions to Phenotypic Heterogeneity in the ALS-FTD Spectrum

Project Summary Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) represent two extremes of an ALS- FTD spectrum, frequently characterized by TDP-43 pathological inclusions and shared genetic risk factors. We have defined normative criteria for characterizing cognitive impairment in ALS and demonstrated that 22% of ALS are cognitively impaired and, in autopsy-confirmed TDP-43 cases, there is an overall >4 hazard ratio for individuals with ALS or FTD onset to develop features of both ALS-FTD. However, prognosis is highly variable across individuals in the ALS-FTD spectrum and risk factors for developing co-occurring motor neuron dysfunction and cognitive impairment are largely unknown, even within C9orf72 repeat expansion families. The overall hypothesis of this proposal is that genetic modifiers of the FTD-ALS spectrum will identify factors predictive of ALS or FTD onset and prognosis for developing ALS-FTD. The discovery of genetic modifiers that contribute to ALS-FTD phenotypic heterogeneity will improve prognostication and clinical trial stratification while enhancing our mechanistic understanding of these highly variable and devastating disorders. This proposal will focus on two strategies for identifying genetic modifiers of binary (ALS vs FTD) and quantitative (neuropsychological and motor) traits. We will leverage the highly integrated Penn Comprehensive ALS Clinic and Penn Frontotemporal Degeneration Center, which have common procedures for neuropsychological and motor phenotyping as well as DNA and biofluid banking. First, we aim to identify polygenic modifiers of cognitive and motor features of ALS-FTD spectrum. We will generate traditional and novel module-based polygenic risk scores (PRS) of common variants associated with “disease-specific” ALS or FTD risk or associated with “domain- specific” heritable traits including cognitive and motor function. We will relate each PRS to cross-sectional and longitudinal neuropsychological and motor/functional scales. We will additionally perform Mendelian Randomization to identify causal associations between heritable traits and disease-specific outcomes. We hypothesize common genetic variation reflected by PRS will modify onset type and quantitative trait measures of cognition and motor impairment. Second, we aim to identify structural variants through long-read sequencing (LRS) of individuals and families that modify cognitive and motor features of the ALS-FTD spectrum. We will use LRS to identify structural variants (SVs) and use rare-variant aggregated and burden tests to identify SVs and genes associated with onset type and quantitative trait measures of cognition and motor. We will additionally use variants component linkage analysis in our well-characterized three-generation pedigrees to identify phenotypic modifiers. We hypothesize both strategies will uncover novel sources of common and rare genetic variation that contribute to heterogeneity in the ALS-FTD spectrum.