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.

C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types

“…Healthy controls included 23 related family members (6 males, 17 females; age range = 28−72 years, mean = 47 years, SD = 13 years). Detailed information on participant inclusion criteria can be found in prior reports ( Lee et al, 2014 ; Bonham et al, 2023 ). The UCSF Committee on Human Research approved the procedures for all participants.…”

“…For example, individuals with ALS display muscle weakness and wasting because of dysfunction and death of upper and lower motor neurons. C9orf72 -FTD typically manifests as bvFTD ( Vatsavayai et al, 2019 ), and anatomically, the cortico-striato-thalamic network ( Lee et al, 2014 ), and medial pulvinar thalamus, specifically, appear to be the primary structures affected ( Sha et al, 2012 ; Yokoyama et al, 2014 ; Vatsavayai et al, 2016 ; Bonham et al, 2023 ). Understanding the genetic landscape of normal C9orf72 - that is, genes that are normally co-expressed with non-expanded C9orf72 - may clarify why certain brain regions are selectively targeted in ALS or FTD (henceforth, ALS/FTD), why some patients may be more likely to develop either ALS/FTD, or both; and which cell-type populations and biological mechanisms are involved.…”

C9orf72gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types

“…For the two patients categorized as other, both showed concerns for motor neuron disease and possibly FTD. Detailed information on participant inclusion criteria can be found in prior reports (Bonham et al, 2023;Lee et al, 2014). The UCSF Committee on Human Research approved the procedures for all participants.…”

“…C9orf72-FTD typically manifests as bvFTD (Vatsavayai et al, 2019). Anatomically, in C9orf72-bvFTD the cortico-striato-thalamic network (Lee et al, 2014), and medial pulvinar thalamus, specifically, appear to be the primary structures affected (Bonham et al, 2023;Sha et al, 2012;Vatsavayai et al, 2016;Yokoyama et al, 2014). Understanding the genetic landscape of normal C9orf72that is, genes that are normally co-expressed with non-expanded C9orf72 -may clarify why certain brain regions are selectively targeted in ALS or FTD (ALS/FTD), why some patients may be more likely to develop either ALS/FTD, or both; and which cell-type populations and biological mechanisms are involved.…”

Allele biased transcription factor binding across human brain regions gives mechanistic insight into eQTLs

“…Gene expression changes occur in essentially every biological process, including the development of diseases (Emilsson et al 2008; Lee and Young 2013) such as neurodegenerative (Bonham et al 2019, 2022; Zhao 2023) and psychiatric conditions (Clifton et al 2019; Mimmack et al 2002; Huang et al 2020). Transcription factors (TFs) and their association with DNA are crucial determinants of gene expression, so identifying factors that influence the association between TFs and DNA is key to understanding variation in gene expression.…”