Correlation of CAG repeat length between the maternal and paternal allele of the Huntingtin gene: evidence for assortative mating

Nopoulos, Peg; Epping, Eric A.; Wassink, Thomas H.; Schlaggar, Bradley L.; Perlmutter, Joel S.

doi:10.1186/1744-9081-7-45

Cited by 5 publications

(5 citation statements)

References 35 publications

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“…In HDGECs, the size of the smaller allele does not appear to influence disease onset, 22 but studies in healthy controls have indicated that the CAG lengths of the two alleles is significantly correlated (albeit within normal limits). 23,24 We also observed this phenomenon and further observed that the CAG length of the small allele is larger in HDGECs than controls. However, our data in HDGECs did not find any correlation between the length of CAG repeats in the two alleles, as observed in controls.…”

Section: Discussionsupporting

confidence: 65%

“…Although it is well established that longer CAG repeats on the larger allele correlate with earlier onset of HD symptoms, the contribution of the smaller allele is less certain. In HDGECs, the size of the smaller allele does not appear to influence disease onset, but studies in healthy controls have indicated that the CAG lengths of the two alleles is significantly correlated (albeit within normal limits) . We also observed this phenomenon and further observed that the CAG length of the small allele is larger in HDGECs than controls.…”

Section: Discussionsupporting

confidence: 65%

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Data Analytics from Enroll‐HD, a Global Clinical Research Platform for Huntington's Disease

Landwehrmeyer

Fitzer‐Attas

Giuliano

et al. 2016

Movement Disord Clin Pract

146

152

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Background: The study of complex neurodegenerative diseases is moving away from hypothesisdriven biological methods toward large scale multimodal approaches, requiring standardized collaborative efforts. Enroll-HD exemplifies such an integrated clinical research platform, designed and implemented to meet the research and clinical needs of Huntington's disease (HD). The aim of this study was to describe the unique organization of Enroll-HD and report baseline data analyses of its core study. Methods: The Enroll-HD platform incorporates electronic data capture, biosampling, and a longitudinal observational study spanning four continents (ClinicalTrials.gov Identifier: NCT01574053). The primary study population includes HD gene expansion carriers (HDGECs; CAG expansion ≥36), subdivided into manifest/ premanifest HD. The control population consists of genotype-negative first-degree relatives and family controls not genetically related. The study includes 10 core clinical assessments covering motor, cognitive, and behavioral domains. Results: This data set comprises 1,534 participants (HDGEC = 1,071; controls = 463). Participant retention was high; 42 participants prematurely withdrew from the study. Mean AE standard deviation SD CAG repeat size was 43.5 AE 3.5 for HDGECs and 19.8 AE 3.4 for controls. Motor and behavioral assessments identified numerical differences between controls and HDGECs (manifest > premanifest > controls). Functional and independence assessments were generally similar for the premanifest and control groups with overlap in range of scores obtained. For the majority of cognitive tests, there were large differences between participants with manifest HD and all other groups. Conclusions: These first data from the Enroll-HD clinical research platform demonstrate the maturity and potential of the platform in collecting high-quality, clinically relevant data. Future data sets will be substantially larger as the platform expands longitudinally and regionally.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionsupporting

confidence: 65%

Data Analytics from Enroll‐HD, a Global Clinical Research Platform for Huntington's Disease

Landwehrmeyer

Fitzer‐Attas

Giuliano

et al. 2016

Movement Disord Clin Pract

146

152

View full text Add to dashboard Cite

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“…In regard specifically to HTT , variation in repeats have been recently been shown to be associated with the lifetime risk for depression, also in a non-linear fashion ( Gardiner et al, 2017 ). In addition, our group has previously reported that CAG repeat below disease threshold is associated with assortative mating ( Nopoulos et al, 2011 ). Assortative mating on intelligence is a well-known phenomenon ( Vinkhuyzen et al, 2012 ), and the findings here provide an additional level of support to the notion that CAG repeats may be related to intelligence, which in turn is related to assortative mating.…”

Section: Discussionmentioning

confidence: 93%

Effect of Trinucleotide Repeats in the Huntington's Gene on Intelligence

et al. 2018

Self Cite

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BackgroundHuntington's Disease (HD) is caused by an abnormality in the HTT gene. This gene includes trinucleotide repeats ranging from 10 to 35, and when expanded beyond 39, causes HD. We previously reported that CAG repeats in the normal range had a direct and beneficial effect on brain development with higher repeats being associated with higher cognitive function. The current study now expands this line of inquiry to evaluate the effects of CAG repeat throughout the entire spectrum of repeats from 15 to 58.MethodsWe evaluated brain function in children ages 6–18 years old. DNA samples were processed to quantify the number of CAG repeats within HTT. Linear regression was used to determine if number of CAG repeats predicted measures of brain function.FindingsThe number of repeats in HTT, had a non-linear effect on a measure of general intelligence with an inverted U shape pattern. Increasing repeat length was associated with higher GAI scores up until roughly 40–41 repeats. After this peak, increasing repeat length was associated with declining GAI scores.InterpretationHTT may confer an advantage or a disadvantage depending upon the repeat length, playing a key role in the determination of intelligence, or causing a uniquely human brain disease.

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“…The mean HTT CAG repeat count of all quantified alleles in our study lay within the expected range between 18.4 and 18.7 as reported for subjects of European descent 1 . So far, the correlation of the ‘longer’ and ‘shorter’ HTT allele has been interpreted as evidence for assortative mating - a mating pattern based on similarities 47,48 . Yet, as the ‘shorter’ allele, by definition, represents the lower boundary for the ‘longer’, and as soon as this definition is lifted, e.g., by permutation analysis with random assignment to two groups, this correlation disappears ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Huntingtin CAG repeat size variations outside the Huntington’s disease complex: associations with depression and anxiety phenotypes and basal ganglia structure

Vater,

Rost,

Eckstein

et al. 2024

Preprint

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Huntington's Disease (HD) is strongly associated with psychiatric symptoms, yet, associations between Huntingtin gene (HTT) CAG repeat size variations and psychiatric phenotypes outside the HD complex are still under-investigated. In this genetic case-control study we compared the distribution of HTT CAG repeat sizes in predefined ranges between patients with major depressive disorder (MDD) (n=2136) and anxiety disorders (ANX) (n=493), and healthy controls (CON) (n=1566). We used regression models to study interactions between the alleles and associations with fine-granular clinical phenotypes and basal ganglia structure. HD mutations in the range of incomplete penetrance (36-39 repeats) were not overrepresented in patients. In participants older than 48 years, 13-20 repeats on both HTT alleles were associated with a reduced ANX risk whereas a 13-20|21-26 combination was associated with an increased ANX risk. Post-hoc analyses confirmed a turning point around 21 repeats and trends in the same direction were detected for MDD. The joint patient|CON analysis of the full spectrum of allele combinations confirmed interaction effects and age-dependent allele|risk profiles. A short-by-long interaction effect and an age-dependent negative correlation of the short allele on the nucleus accumbens volume was detected, independently of the diagnostic group. In conclusion, we revealed that HTT CAG repeat sizes of both alleles in the non-HD range modulate the susceptibility for common psychiatric disorders and basal ganglia structure in an age-dependent way, displaying that normal variation of the functionally diverse wildtype huntingtin protein may already impact brain function.

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Correlation of CAG repeat length between the maternal and paternal allele of the Huntingtin gene: evidence for assortative mating

Cited by 5 publications

References 35 publications

Data Analytics from Enroll‐HD, a Global Clinical Research Platform for Huntington's Disease

Data Analytics from Enroll‐HD, a Global Clinical Research Platform for Huntington's Disease

Effect of Trinucleotide Repeats in the Huntington's Gene on Intelligence

Huntingtin CAG repeat size variations outside the Huntington’s disease complex: associations with depression and anxiety phenotypes and basal ganglia structure

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