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Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease.

ABSTRACT: Huntington disease (HD) is a neurodegenerative disorder that is caused by a CAG repeat expansion in HTT. The length of this repeat, however, only explains a proportion of the variability in age of onset in patients. Genome-wide association studies have identified modifiers that contribute toward a proportion of the observed variance. By incorporating tissue-specific transcriptomic information with these results, additional modifiers can be identified. We performed a transcriptome-wide association study assessing heritable differences in genetically determined expression in diverse tissues, with genome-wide data from over 4000 patients. Functional validation of prioritized genes was undertaken in isogenic HD stem cells and patient brains. Enrichment analyses were performed with biologically relevant gene sets to identify the core pathways. HD-associated gene coexpression modules were assessed for associations with neurological phenotypes in an independent cohort and to guide drug repurposing analyses. Transcriptomic analyses identified genes that were associated with age of HD onset and displayed colocalization with gene expression signals in brain tissue (FAN1, GPR161, PMS2, SUMF2), with supporting evidence from functional experiments. This included genes involved in DNA repair, as well as novel-candidate modifier genes that have been associated with other neurological conditions. Further, cortical coexpression modules were also associated with cognitive decline and HD-related traits in a longitudinal cohort. In summary, the combination of population-scale gene expression information with HD patient genomic data identified novel modifier genes for the disorder. Further, these analyses expanded the pathways potentially involved in modifying HD onset and prioritized candidate therapeutics for future study.

SUBMITTER: Wright GEB

PROVIDER: S-EPMC7530525 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease.

Wright Galen E B GEB Caron Nicholas S NS Ng Bernard B Casal Lorenzo L Casazza William W Xu Xiaohong X Ooi Jolene J Pouladi Mahmoud A MA Mostafavi Sara S Ross Colin J D CJD Hayden Michael R MR

Human molecular genetics 20200901 16

Huntington disease (HD) is a neurodegenerative disorder that is caused by a CAG repeat expansion in HTT. The length of this repeat, however, only explains a proportion of the variability in age of onset in patients. Genome-wide association studies have identified modifiers that contribute toward a proportion of the observed variance. By incorporating tissue-specific transcriptomic information with these results, additional modifiers can be identified. We performed a transcriptome-wide associatio ...[more]

PMID: 32898862

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Project description:The identification of molecular biomarkers in CSF from individuals affected by Huntington disease may help improve predictions of disease onset, better define disease progression and could facilitate the evaluation of potential therapies. The primary objective of our study was to investigate novel CSF protein candidates and replicate previously reported protein biomarker changes in CSF from Huntington disease mutation carriers and healthy controls. Our secondary objective was to compare the discriminatory potential of individual protein analytes and combinations of CSF protein markers for stratifying individuals based on the severity of Huntington disease. We conducted a hypothesis-driven analysis of 26 pre-specified protein analytes in CSF from 16 manifest Huntington disease subjects, eight premanifest Huntington disease mutation carriers and eight healthy control individuals using parallel-reaction monitoring mass spectrometry. In addition to reproducing reported changes in previously investigated CSF biomarkers (NEFL, PDYN, and PENK), we also identified novel exploratory CSF proteins (C1QB, CNR1, GNAL, IDO1, IGF2, and PPP1R1B) whose levels were altered in Huntington disease mutation carriers and/or across stages of disease. Moreover, we report strong associations of select CSF proteins with clinical measures of disease severity in manifest Huntington disease subjects (C1QB, CNR1, NEFL, PDYN, PPP1R1B, and TTR) and with years to predicted disease onset in premanifest Huntington disease mutation carriers (ALB, C4B, CTSD, IGHG1, and TTR). Using receiver operating characteristic curve analysis, we identified PENK as being the most discriminant CSF protein for stratifying Huntington disease mutation carriers from controls. We also identified exploratory multi-marker CSF protein panels that improved discrimination of premanifest Huntington disease mutation carriers from controls (PENK, ALB and NEFL), early/mid-stage Huntington disease from premanifest mutation carriers (PPP1R1B, TTR, CHI3L1, and CTSD), and late-stage from early/mid-stage Huntington disease (CNR1, PPP1R1B, BDNF, APOE, and IGHG1) compared with individual CSF proteins. In this study, we demonstrate that combinations of CSF proteins can outperform individual markers for stratifying individuals based on Huntington disease mutation status and disease severity. Moreover, we define exploratory multi-marker CSF protein panels that, if validated, may be used to improve the accuracy of disease-onset predictions, complement existing clinical and imaging biomarkers for monitoring the severity of Huntington disease, and potentially for assessing therapeutic response in clinical trials. Additional studies with CSF collected from larger cohorts of Huntington disease mutation carriers are needed to replicate these exploratory findings.

Dataset Information

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease.

Publications

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease.

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