Leiden University Scholarly Publications

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Gardiner, S.L. (2019)

Huntington disease and other polyglutamine diseases : using CAG repeat variations to explain missing heritability

Doctoral Thesis
Many common disorders, including depression, dementia and obesity are for a large part heritable. Despite the fact that genome-wide association studies (GWAS) have contributed substantially to unraveling the genetic architecture of these polygenetic disorders, a large amount of ‘missing heritability’ remains. A possible explanation is that GWAS, aside single-nucleotide polymorphisms cannot assess the contribution of other important genetic polymorphisms, especially tandem repeats. Tandem repeats constitute 3% of the human genome. Nine hereditary neurodegenerative diseases, known as polyglutamine diseases, including Huntington disease (HD), are the most prevalent disorders associated with tandem repeat variations. These diseases are caused by an elongated cytosine-adenine-guanine (CAG) repeat sequence in the respective polyglutamine disease-associated gene (PDAG). In this dissertation, we provide ample evidence that CAG repeat variations within the ‘normal’ range in PDAGs can...Show moreMany common disorders, including depression, dementia and obesity are for a large part heritable. Despite the fact that genome-wide association studies (GWAS) have contributed substantially to unraveling the genetic architecture of these polygenetic disorders, a large amount of ‘missing heritability’ remains. A possible explanation is that GWAS, aside single-nucleotide polymorphisms cannot assess the contribution of other important genetic polymorphisms, especially tandem repeats. Tandem repeats constitute 3% of the human genome. Nine hereditary neurodegenerative diseases, known as polyglutamine diseases, including Huntington disease (HD), are the most prevalent disorders associated with tandem repeat variations. These diseases are caused by an elongated cytosine-adenine-guanine (CAG) repeat sequence in the respective polyglutamine disease-associated gene (PDAG). In this dissertation, we provide ample evidence that CAG repeat variations within the ‘normal’ range in PDAGs can affect various aspects of disease, including the age of onset in HD, cognitive function, depression and body mass index. Finally, we found a relatively large prevalence of intermediate and pathological PDAG alleles in the general population. Therefore, we provided support for the role of repetitive DNA polymorphisms in elucidating the ‘missing heritability’ of polygenetic disorders and emphasized the necessity to include these variations in future genetic research.Show less
Age of onset
Alzheimer disease
Cognitive function
Tandem repeats
Polyglutamine disease-associated gene
Depression
Body mass index
Spinocerebellar ataxia
Dentatorubral-pallidoluysion atrophy
Spinal and bulbar muscular atrophy
All authors
Gardiner, S.L.
Supervisor
Roos, R.A.C.
Co-supervisor
Aziz, N.A.
Committee
Maarel, S.M. van der; Flier, W.M. van der; Verhey, F.R.J.
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2019-10-10
ISBN (print)
9789461829627

Funding

Sponsorship
Research: the Netherlands Organization of Scientific Research the European Union (Horizon 2020) Printing: Leiden University Medical Centre ADCA Vereniging Nederland Vereniging van Huntington the department of Neurology at the Reinier de Graaf Gasthuis