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

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.

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Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

The Lancet Neurology ◽

10.1016/s1474-4422(17)30161-8 ◽

2017 ◽

Vol 16 (9) ◽

pp. 701-711 ◽

Cited By ~ 114

Author(s):

Davina J Hensman Moss ◽

Antonio F Pardiñas ◽

Douglas Langbehn ◽

Kitty Lo ◽

Blair R Leavitt ◽

...

Keyword(s):

Huntington's Disease ◽

Association Study ◽

Huntington’S Disease ◽

Disease Progression ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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Mutant Huntingtin Affects Diabetes and Alzheimer’s Markers in Human and Cell Models of Huntington’s Disease

Cells ◽

10.3390/cells8090962 ◽

2019 ◽

Vol 8 (9) ◽

pp. 962 ◽

Cited By ~ 1

Author(s):

Gepoliano Chaves ◽

John Stanley ◽

Nader Pourmand

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Genome Wide Association Study ◽

Cell Model ◽

Statistical Significance ◽

Mutant Huntingtin ◽

Rna Seq ◽

Genome Wide ◽

A Genome ◽

Reliable Model

A higher incidence of diabetes was observed among family members of individuals affected by Huntington’s Disease with no follow-up studies investigating the genetic nature of the observation. Using a genome-wide association study (GWAS), RNA sequencing (RNA-Seq) analysis and western blotting of Rattus norvegicus and human, we were able to identify that the gene family of sortilin receptors was affected in Huntington’s Disease patients. We observed that less than 5% of SNPs were of statistical significance and that sortilins and HLA/MHC gene expression or SNPs were associated with mutant huntingtin (mHTT). These results suggest that ST14A cells derived from R. norvegicus are a reliable model of HD, since sortilins were identified through analysis of the transcriptome in these cells. These findings help highlight the genes involved in mechanisms targeted by diabetes drugs, such as glucose transporters as well as proteins controlling insulin release related to mHTT. To the best of our knowledge, this is the first GWAS using RNA-Seq data from both ST14A rat HD cell model and human Huntington’s Disease.

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

Journal of Huntington s Disease ◽

10.3233/jhd-210485 ◽

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.

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Genome-wide association study of pathological gambling

European Psychiatry ◽

10.1016/j.eurpsy.2016.04.001 ◽

2016 ◽

Vol 36 ◽

pp. 38-46 ◽

Cited By ~ 20

Author(s):

M. Lang ◽

T. Leménager ◽

F. Streit ◽

M. Fauth-Bühler ◽

J. Frank ◽

...

Keyword(s):

Alcohol Dependence ◽

Pathological Gambling ◽

Huntington's Disease ◽

Association Study ◽

Huntington’S Disease ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Polygenic Risk ◽

Genome Wide ◽

Genetic Overlap

AbstractBackgroundPathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence.MethodsFour hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence.ResultsNo genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value = 6.63 × 10−3); 5′-adenosine monophosphate-activated protein kinase signalling (P-value = 9.57 × 10−3); and apoptosis (P-value = 1.75 × 10−2) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status.ConclusionsThe present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies.

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Clinicopathological differences between the motor onset and psychiatric onset of Huntington's disease, focusing on the nucleus accumbens

Neuropathology ◽

10.1111/neup.12578 ◽

2019 ◽

Vol 39 (5) ◽

pp. 331-341 ◽

Cited By ~ 1

Author(s):

Mitsuaki Hirano ◽

Shuji Iritani ◽

Hiroshige Fujishiro ◽

Youta Torii ◽

Chikako Habuchi ◽

...

Keyword(s):

Nucleus Accumbens ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Motor Onset

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

Journal of Huntington s Disease ◽

10.3233/jhd-200429 ◽

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.

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