Genetic Modifiers in Huntington Disease


Huntington disease (HD) is a neurodegenerative disorder that is caused by an elongation of a normally occurring polyglutamine stretch within the huntingtin (HTT) protein. Since the mutation was first identified, multiple HD‐disease‐modifying gene candidates that can hasten or delay age of onset (AO) have been discovered. For the past several decades, candidate disease‐modifying genes have been chosen for investigation based on functionality or prior implication in the disease process. More recent approaches take advantage of newly available genomic‐wide assays to identify changes as small as single‐nucleotide polymorphisms (SNPs) in other parts of the genome. New information regarding disease‐modifying genes will continue to elucidate potential HD therapeutic candidates.

Key Concepts

  • Huntington disease is a neurodegenerative disease that results from excess CAG trinucleotide repeats in exon 1 of the HD gene, which is located in chromosome 4p16.3 and encodes the HTT protein.
  • The number of CAG repeats in the HD gene inversely affects the age of onset (AO) in HD patients.
  • Genetic modifiers are identified genes that have the ability to either hasten or delay AO of HD; however, the exact mechanism of many of these genes in association with the disease is unknown.
  • HD genetic modifiers can significantly delay specific physiological HD symptoms, such as chorea.
  • Some HD genetic modifiers can alter HD AO by up to 8 years.
  • Genetic modifiers have been discovered by either the candidate approach, which involves exploring genes known to be associated with the HTT protein and genotyping any variants, or via a more unbiased genomic approach, which involves a broad search for genes that are not known to be associated with the HTT protein.
  • Modifiers that affect HD do not necessarily need to be within close vicinity of the actual gene, but can be distributed elsewhere in the genome, even in noncoding regions.

Keywords: genome wide association; gain of function; loss of function; polyglutamine repeat disease; age of onset; huntingtin (HTT); chorea; genetic disease modifiers; Huntington disease (HD); triplet repeat disorder

Figure 1. Huntington disease is characterised by alterations in motor control, cognitive function and emotional well‐being.
Figure 2. Age of onset (AO) is strongly correlated with the number of CAG repeats found in HD exon 1. An increase in CAG repeats results in an earlier AO in HD patients. See also: Huntington Disease
Figure 3. Polymorphisms in other genes found on human chromosome 4 can affect HD age of onset, including MSX1, PPARGC1A and UCHL1. UCHL1 has been shown to function as a genetic modifier of HD in some populations (Metzger et al., ), but not in others (Andresen et al., ).


Andresen JM, Gayán J, Cherny SS, et al. (2007) Replication of twelve association studies for Huntington's disease residual age of onset in large Venezuelan kindreds. Journal of Medical Genetics 44 (1): 44–50.

Arning L, Monté D, Hansen W, et al. (2008) ASK1 and MAP2K6 as modifiers of age at onset in Huntington's disease. Journal of Molecular Medicine 86 (4): 485–490.

Arning L and Epplen JT (2012) Genetic modifiers of Huntington's disease: beyond CAG. Future Neurology 7 (1): 93–109.

Bečanović K, Nørremølle A, Neal SJ, et al. (2015) A SNP in the HTT promoter alters NF‐κB binding and is a bidirectional genetic modifier of Huntington disease. Nature Neuroscience 18 (6): 807–816.

Berger F, Vaslin L, Belin L, et al. (2013) The impact of single-nucleotide polymorphisms (SNPs) in OGG1 and XPC on the age at onset of Huntington disease. Mutation Research 755 (2): 115–9.

Botas J (2003) Neurodegenerative diseases: insights from Drosophila and mouse models. In: Mallet J and Christen Y (eds) Neurosciences at the Postgenomic Era: Research and Perspectives in Neurosciences, pp. 85–104. Heidelberg, Germany: Springer.

Clabough EBD (2013) Huntington's disease: the past, present, and future search for disease modifiers. Yale Journal of Biology and Medicine 86 (2): 217–233.

Chattopadhyay B, Baksi K, Mukhopadhyay S and Bhattacharyya NP (2005) Modulation of age at onset of Huntington disease patients by variations in TP53 and human caspase activated DNase (hCAD) genes. Neuroscience Letters 374 (2): 81–86.

Dhaenens CM, Burnouf S, Simonan C, et al. (2009) A genetic variation in the ADORA2A gene modifies age of onset in Huntington's disease. Neurobiology of Disease 35: 474–476.

Djoussé L, Knowlton B, Hayden MR, et al. (2004) Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16. Neurogenetics 5: 109–114.

Edmond YW, Jamal N, Gutekunst CA, et al. (2002) Targeted disruption of Huntingtin‐associated protein‐1 (Hap1) results in postnatal death due to depressed feeding behavior. Human Molecular Genetics 11 (8): 945–959.

Gusella JF, Wexler NS, Conneally PM, et al. (1983) A polymorphic DNA marker genetically linked to Huntington's disease. Nature 306 (5940): 234–238.

Gusella JF (2001) Huntington disease. In: Encyclopedia of Life Sciences (ELS). Chichester: John Wiley & Sons, Ltd. DOI: 10.1038/npg.els.0000147.

Gusella JF and MacDonald M (2007) Genetic criteria for Huntington's disease pathogenesis. Brain Research Bulletin 72: 78–82.

Holbert S, Denghien I, Klechle T, et al. (2001) The Gln‐Ala repeat transcriptional activator CA150 with huntingtin: neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis. PNAS 13: 1811–1816.

Karadima G, Dimovasili C, Koutsis G, Vassilopoulos D and Panas M (2012) Age at onset in Huntington's disease: replication study on the association of HAP1. Parkinsonism Related Disorders 18 (9): 1027–1028.

Kloster E, Saft C, Epplen JT and Arning L (2013) CNR1 variation is associated with the age at onset in Huntington disease. European Journal of Medical Genetics 56: 416–419.

Li JL, Hayden MR, Almqvist EW, et al. (2003) A genome scan for modifiers of age at onset in Huntington disease: The HDMAPS study. American Journal of Human Genetics 73 (3): 682–7.

Metzger S, Bauer P, Tomiuk J, et al. (2005) The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington's disease. Neurogenetics 7 (1): 27–30.

Metzger S, Rong J, Nguyen HP, et al. (2008) Huntingtin‐associated protein‐1 is a modifier of the age‐at‐onset of Huntington's disease. Human Molecular Genetics 17: 1137–1146.

Nalls MA, Pankratz N, Lill CM, et al. (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nature Genetics 46 (9): 989–93.

Nasir J, Floresco SB, O'Kusky JR, et al. (1995) Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81: 811–823.

Pinto R, Dragileva E, Kirby A, et al. (2013) Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome‐wide and candidate approaches. PLoS Genetics 9 (10): 1–19.

Rubinsztein DC, Leggo J, Chiano M, et al. (1997) Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. PNAS 94: 3872–3876.

Ramos EM, Latourelle JC, Lee JH, et al. (2012) Population stratification may bias analysis of PGC‐1 as a modifier of age at Huntington disease motor onset. Human Genetics 131: 1833–1840.

Ramos E, Kovalenko M, Guide J, et al. (2015) Chromosome substitution strain assessment of a Huntington's disease modifier locus. Mammalian Genome 26 (3–4): 119–130.

Shema R, Kulicke R, Cowley G, et al. (2015) Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington's disease. Proceedings of the National Academy of Sciences of the United States of America 112: 268–272.

Stine OC, Pleasant N, Franz ML, et al. (1993) Correlation between the onset age of Huntington's disease and length of the trinucleotide repeat in IT‐15. Human Molecular Genetics 2 (10): 1547–1549.

Sudmant PH, Rausch T, Gardner EJ, et al. (2015) An integrated map of structural variation in 2,504 human genomes. Nature 526 (7571): 75–81.

Taherzadeh‐Fard E, Saft C, Wieczorek S, Epplen JT and Arning L (2010) Age at onset in Huntington's disease: replication study on the associations of ADORA2A, HAP1 and OGG1. Neurogenetics 11 (4): 435–439.

The Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72: 971–984.

The Genetic Modifiers of Huntington's Disease (GeM‐HD) Consortium (2015) Identification of genetic factors that modify clinical onset of Huntington's disease. Cell 162: 516–526.

Weydt P, Soyal SM, Gellera C, et al. (2009) The gene coding for PGC‐1α modifies age at onset in Huntington's disease. Molecular Neurodegeneration 4: 3. DOI: 10.1186/1750-1326-4-3.

Weydt P, Soyal SM, Landwehrmeyer GB and Patsch W (2014) A single nucleotide polymorphism in the coding region of PGC‐1α is a male‐specific modifier of Huntington disease age‐at‐onset in a large European cohort. BMC Neurology 14: 1–14.

White JK, Auerbach W, Duyao MP, et al. (1997) Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nature Genetics 17: 404–410.

Valcárcel‐Ocete L, Alkorta‐Aranburu G, Iriondo M, et al. (2015) Exploring genetic factors involved in Huntington disease age of onset: E2F2 as a new potential modifier gene. PLoS One 10: 1–14.

Zeitlin S, Liu JP, Chapman DL, Papaioannou VE and Efstratiadis A (1995) Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nature Genetics 11: 155–163.

Zeng W, Gillis T, Hakky M, et al. (2006) Genetic analysis of the GRIK2 modifier effect in Huntington disease. BMC Neuroscience 7: 62–71.

Further Reading

Hmida‐Ben Brahim D, Chourabi M, Amor S, Harrabi I, et al. (2014) Modulation at age of onset in Tunisian Huntington disease patients: implication of new modifier genes. Genetic Research International 210418: 1–5.

Kaltenbach LS, Romero E, Becklin RR, et al. (2007) Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genetics 3 (5).

Lunkes A, Yvert G, Trottier Y, Devys D and Mandel JL (2001) Pathological mechanisms in Huntington's disease and other polyglutamine expansion diseases. In: Beyreuther K, Christen Y and Masters C (eds) Neurodegenerative Disorders: Loss of Function through Gain of Function: Research and Perspectives in Alzheimer's Disease, pp. 107–118. Berlin Heidelberg: Springer.

MacDonald M and Gusella J (2009) Huntington's disease: the case for genetic modifiers. Genome Medicine 1: 80.

Metzger S, Walter C, Riess O, et al. (2013) The V471A polymorphism in autophagy‐related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients. PLoS One 8 (7): e68951.

Miller JP and Hughes RE (2011) Protein interactions and target discovery in Huntington's disease. In: Lo DC and Hughes RE (eds) Neurobiology of Huntington's Disease: Applications to Drug Discovery, pp. 55–76. Boca Raton, FL: CRC Press.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Clabough, Erin BD, Thompson, Jefferson C, Lau, James H, Savarese, Melchior F, Harris, Evan C, Manos, Sean T, Kyle, Charles T, Meinhardt, John T, Sheffield, John W, Boudin, Michael D, Abdi, Myshake S, Mohay, John AS, Harriss, Robert W, Luck, Mason E, Owens, Alan M, and Britt, John W(Feb 2016) Genetic Modifiers in Huntington Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026547]