scholarly journals Association Analysis of Chromosome X to Identify Genetic Modifiers of Huntington’s Disease

2021 ◽  
pp. 1-9
Author(s):  
Eun Pyo Hong ◽  
Michael J. Chao ◽  
Thomas Massey ◽  
Branduff McAllister ◽  
Sergey Lobanov ◽  
...  
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Association Analysis ◽  
X Chromosome ◽  
Age At Onset ◽  
Cag Repeat ◽  
Chromosome X ◽  
Repeat Instability ◽  
Genome Wide ◽  
Dna Maintenance

Background: Huntington’s disease (HD) is caused by an expanded (>35) CAG trinucleotide repeat in huntingtin (HTT). Age-at-onset of motor symptoms is inversely correlated with the size of the inherited CAG repeat, which expands further in brain regions due to somatic repeat instability. Our recent genetic investigation focusing on autosomal SNPs revealed that age-at-onset is also influenced by genetic variation at many loci, the majority of which encode genes involved in DNA maintenance/repair processes and repeat instability. Objective: We performed a complementary association analysis to determine whether variants in the X chromosome modify HD. Methods: We imputed SNPs on chromosome X for ∼9,000 HD subjects of European ancestry and performed an X chromosome-wide association study (XWAS) to test for association with age-at-onset corrected for inherited CAG repeat length. Results: In a mixed effects model XWAS analysis of all subjects (males and females), assuming random X-inactivation in females, no genome-wide significant onset modification signal was found. However, suggestive significant association signals were detected at Xq12 (top SNP, rs59098970; p-value, 1.4E-6), near moesin (MSN), in a region devoid of DNA maintenance genes. Additional suggestive signals not involving DNA repair genes were observed in male- and female-only analyses at other locations. Conclusion: Although not genome-wide significant, potentially due to small effect size compared to the power of the current study, our data leave open the possibility of modification of HD by a non-DNA repair process. Our XWAS results are publicly available at the updated GEM EURO 9K website hosted at https://www.hdinhd.org/ for browsing, pathway analysis, and data download.

scholarly journals Huntington's disease age at motor onset is modified by the tandem hexamer repeat in TCERG1

2021 ◽  
Author(s):  
Sergey V. Lobanov ◽  
Branduff McAllister ◽  
Mia McDade-Kumar ◽  
G. Bernhard Landwehrmeyer ◽  
Anne E. Rosser ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Genome Wide Association Study ◽  
Age At Onset ◽  
Sequencing Data ◽  
Genome Wide ◽  
Novel Method ◽  
One Year ◽  
Dna Maintenance ◽  
Motor Onset

Background: Huntington's disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington's disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. Methods: We developed a novel method for calling perfect and imperfect repeats from exome sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington's disease via regression analysis. Results: We found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1x10-9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. Conclusions: The association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.

scholarly journals Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes

2009 ◽  
Vol 33 (1) ◽  
pp. 37-47 ◽  
Author(s):  
Ella Dragileva ◽  
Audrey Hendricks ◽  
Allison Teed ◽  
Tammy Gillis ◽  
Edith T. Lopez ◽  
...  
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Dna Repair Genes ◽  
Repeat Instability ◽  
Repair Genes

scholarly journals The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

2021 ◽  
Vol 10 (1) ◽  
pp. 7-33
Author(s):  
Darren G. Monckton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Human Genetics ◽  
Age At Onset ◽  
Cag Repeat ◽  
Model Systems ◽  
Causative Mutation ◽  
Inverse Association ◽  
Independent Manner ◽  
Dna Mismatch

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

scholarly journals Genome-wide association analysis of age at onset and psychotic symptoms in bipolar disorder

2011 ◽  
Vol 156 (3) ◽  
pp. 370-378 ◽  
Author(s):  
Pamela Belmonte Mahon ◽  
Mehdi Pirooznia ◽  
Fernando S. Goes ◽  
Fayaz Seifuddin ◽  
Jo Steele ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Association Analysis ◽  
Age At Onset ◽  
Genome Wide Association ◽  
Psychotic Symptoms ◽  
Genome Wide Association Analysis ◽  
Genome Wide

scholarly journals Genetic Contributors to Intergenerational CAG Repeat Instability in Huntington’s Disease Knock-In Mice

Genetics ◽  
2016 ◽  
Vol 205 (2) ◽  
pp. 503-516 ◽  
Author(s):  
João Luís Neto ◽  
Jong-Min Lee ◽  
Ali Afridi ◽  
Tammy Gillis ◽  
Jolene R. Guide ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Repeat Instability

scholarly journals New developments in Huntington’s disease and other triplet repeat diseases: DNA repair turns to the dark side

2020 ◽  
Vol 4 (4) ◽  
Author(s):  
Robert S. Lahue
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Model Systems ◽  
Triplet Repeat ◽  
Maximal Effect ◽  
Huntingtin Protein ◽  
Dna Repair Proteins ◽  
Repeat Expansions

Abstract Huntington’s disease (HD) is a fatal, inherited neurodegenerative disease that causes neuronal death, particularly in medium spiny neurons. HD leads to serious and progressive motor, cognitive and psychiatric symptoms. Its genetic basis is an expansion of the CAG triplet repeat in the HTT gene, leading to extra glutamines in the huntingtin protein. HD is one of nine genetic diseases in this polyglutamine (polyQ) category, that also includes a number of inherited spinocerebellar ataxias (SCAs). Traditionally it has been assumed that HD age of onset and disease progression were solely the outcome of age-dependent exposure of neurons to toxic effects of the inherited mutant huntingtin protein. However, recent genome-wide association studies (GWAS) have revealed significant effects of genetic variants outside of HTT. Surprisingly, these variants turn out to be mostly in genes encoding DNA repair factors, suggesting that at least some disease modulation occurs at the level of the HTT DNA itself. These DNA repair proteins are known from model systems to promote ongoing somatic CAG repeat expansions in tissues affected by HD. Thus, for triplet repeats, some DNA repair proteins seem to abandon their normal genoprotective roles and, instead, drive expansions and accelerate disease. One attractive hypothesis—still to be proven rigorously—is that somatic HTT expansions augment the disease burden of the inherited allele. If so, therapeutic approaches that lower levels of huntingtin protein may need blending with additional therapies that reduce levels of somatic CAG repeat expansions to achieve maximal effect.

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