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Approved research

Impacts of huntingtin CAG repeats and modifiers of neurodegeneration in Huntington's disease on human phenotypes

Principal Investigator: Jong-Min Lee
Approved Research ID: 18288
Approval date: April 1st 2017

Lay summary

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded huntingtin CAG repeat. Age at onset of HD is primarily determined by size of CAG repeat. However, HD is modified by other factors resulting in earlier or later age at onset compared to expectation. We recently discovered common genetic variants significantly associated with modification of the rate of neurodegeneration in HD. Although those variations were discovered in HD, they may influence the rate of neurodegeneration and other phenotypes in non-HD. Thus, we aim to investigate the impacts of genetic modifiers of HD on various phenotypes. We planned to stratify UK Biobank subjects based on polygenic modification score using HD modifier SNPs to identify phenotypes associated with modification of HD neurodegeneration. Potentially, this project may reveal association between phenotypes in UK Biobank data and genes that alter the rate of neurodegeneration in HD. Such associations may imply genetic commonality, and therefore therapeutic treatments developed for those diseases may be applied to HD. Vice versa, drugs for HD can be re-purposed for those associated phenotypes. This study therefore contributes to human health by providing insights into the genetic foundation of HD modification and other human phenotypes. We have identified genetic loci significantly associated with modification of the rate of neurodegeneration in HD, and subsequently developed parameters to calculate polygenic risk score indicative of individual levels of modification of neuropathology in HD. UK Biobank genotype data will be analyzed to modification score for neurodegeneration in HD using parameters that we recently developed. Then, subject groups in UK Biobank data stratified based on modification score will be compared to identify phenotypes that are significantly associated with modification of HD neurodegeneration. Associated phenotypes support shared genetic components with modification of neurodegeneration in HD. Since the proposed analysis require UK Biobank genetic data including rare variations, we propose to analyze the full cohort data including genotypes and phenotypes. We do not request biosamples.