Journal article
Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease
Cell, Vol.162(3), pp.516-526
07/30/2015
DOI: 10.1016/j.cell.2015.07.003
PMCID: PMC4524551
PMID: 26232222
Abstract
As a Mendelian neurodegenerative disorder, the genetic risk of Huntington's disease (HD) is conferred entirely by an HTT CAG repeat expansion whose length is the primary determinant of the rate of pathogenesis leading to disease onset. To investigate the pathogenic process that precedes disease, we used genome-wide association (GWA) analysis to identify loci harboring genetic variations that alter the age at neurological onset of HD. A chromosome 15 locus displays two independent effects that accelerate or delay onset by 6.1 years and 1.4 years, respectively, whereas a chromosome 8 locus hastens onset by 1.6 years. Association at MLH1 and pathway analysis of the full GWA results support a role for DNA handling and repair mechanisms in altering the course of HD. Our findings demonstrate that HD disease modification in humans occurs in nature and offer a genetic route to identifying in-human validated therapeutic targets in this and other Mendelian disorders.
Details
- Title: Subtitle
- Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease
- Creators
- Jong-Min LeeVanessa C. WheelerMichael J. ChaoJean Paul G. VonsattelRicardo Mouro PintoDiane LucenteKawther Abu-ElneelEliana Marisa RamosJayalakshmi Srinidhi MysoreTammy GillisMarcy E. MacDonaldJames F. GusellaDenise HaroldTimothy C. StoneValentina Escott-PriceJun HanAlexey VedernikovPeter HolmansLesley JonesSeung KwakMithra MahmoudiMichael OrthG. Bernhard LandwehrmeyerJane S. PaulsenE. Ray DorseyIra ShoulsonRichard H. MyersGenetic Modifiers of Huntington’s Disease (GeM-HD) Consortium
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.162(3), pp.516-526
- Publisher
- Elsevier
- DOI
- 10.1016/j.cell.2015.07.003
- PMID
- 26232222
- PMCID
- PMC4524551
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Number of pages
- 11
- Grant note
- R01NS073947 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Prana Biotechnology Ltd G0801418; MR/L010305/1 / Medical Research Council (UK); UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Auspex Pharmaceuticals G0801418 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission MR/L023784/2 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) CHDI Foundation X01HG006074; U01NS082079; R01NS091161; R01HG002449; P50NS016367 / National Institutes of Health (USA); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HG002449 / NATIONAL HUMAN GENOME RESEARCH INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI)
- Language
- English
- Date published
- 07/30/2015
- Academic Unit
- Psychiatry; Psychological and Brain Sciences
- Record Identifier
- 9984383295302771
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