Radiogenomics ofC9orf72Expansion Carriers Reveals Global Transposable Element Derepression and Enables Prediction of Thalamic Atrophy and Clinical Impairment

Abstract

Hexanucleotide repeat expansion (HRE) withinC9orf72is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, includingC9orf72HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheralC9orf72expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects ofC9orf72HRE and clinical diagnosis (n= 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheralC9orf72expression, TE activation, thalamic atrophy, and clinical severity (n= 114 individuals, male and female). We confirmed global thalamic atrophy and reducedC9orf72expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed thatC9orf72expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 elementL1HS.L1HSlevels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated thatC9orf72levels relate to clinical severity, and identified marked derepression of TEs, includingL1HS, which predicted atrophy of FTD-relevant thalamic nuclei.SIGNIFICANCE STATEMENTPathogenic repeat expansion inC9orf72is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction ofC9orf72in blood and found broad dysregulation of transposable elements—genetic elements typically repressed in the human genome—in symptomaticC9orf72expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD.C9orf72expression was also associated with clinical severity, suggesting that peripheralC9orf72levels capture disease-relevant information.