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Repeat polymorphisms as genetic modifiers of brain function in healthy subjects and Huntington disease mutation carriers

Periodic Reporting for period 1 - BRAIN REPEATS (Repeat polymorphisms as genetic modifiers of brain function in healthy subjects and Huntington disease mutation carriers)

Reporting period: 2016-10-01 to 2017-09-30

What is the problem/issue being addressed?
Many genetic association studies, mainly genome-wide association studies (GWAS), have been performed to identify genetic risk factors for neuropsychiatric diseases. However, the single-nucleotide polymorphisms identified through this approach only account for a small fraction of the genetic determinants, giving rise to the problem of ‘missing heritability’. A main reason is likely that GWAS cannot assess the contribution of other important genetic polymorphisms, especially DNA repeat expansions. Expansions of simple repeat sequences in genomic DNA have been associated with many hereditary brain disorders, but their association with (normal) brain structure and function is largely unknown. Among expanded repeat disorders polyglutamine diseases are the most prevalent. These diseases are characterized by a trinucleotide (cytosine-adenine-guanine (CAG)) repeat expansion in the translated regions of otherwise unrelated genes, resulting in proteins with expanded polyglutamine domains. In this project we strive to elucidate part of this 'missing heritability' problem of complex neuropschiatric disorders by evaluating the role of tandem repeat variations, especially CAG repeat polymorphisms, as modulators of brain structure and function.

What is the problem/issue being addressed?
Neuropsychiatric disorders such as dementia and depression are among the most common diseases worldwide and belong to the top 10 leading causes of disability in high-income countries. However, current treatments are mainly symptomatic and far from optimal. In order to devise more effective therapeutic and preventive strategies a better understanding of their pathogenesis is essential. A vital step in elucidating the pathogenesis of these disorders is to gain more insight into the genetic determinants of normal as well as perturbed brain function. This project will help to identify novel genetic determinants of brain structure and function and, thereby, help to design and develop new treatments for these devastating diseases in the future.

What are the overall objectives?
The key objective of this proposal is thus to evaluate the effects of CAG repeat polymorphisms in polyglutamine disease-associated genes (PDAGs) on brain structure and function, both in healthy controls and Huntington disease (HD) mutation carriers.
- A personal career development plan was written at the start of the project
- The DNA samples from two large cohorts have been genotyped with respect to the CAG repeat sizes in the nine PDAGs.
- Brain MRI data with respect to morphometric and connectivity measures have been analyzed.
- Statistical assessment of the associations between the genotype, imaging and phenotype data in controls and HD mutation carriers has been completed.
- Part of the scientific work resulting from this project has already been published (please refer to the publciation section) and another comprehensive scientific publication, in the form of a journal article, is currently being prepared.
- Attended weekly research meetings and clinical seminars offered by the UCL HD research centre and the Institute of Neurology
- Participated in the UCL Institute of Neurology QS course: “Statistical Parametric Mapping for fMRI and MRI/VBM”
- The results obtained in this project are likely to substantially advance the field of genetics of complex neuropsychiatric disorder, particularly depression and dementia, beyond the state of the art. Our results provide firm support for the role of tandem repeat polymorphism as important novel modifiers of brain structure and function. Therefore, our results are of direct relevance for a better understanding of neuropschiatric disorders, and thereby, are likely to help the design and development of novel therapies for these common disorders. Indeed, neuropsychiatric disorders such as dementia and depression are among the most common human diseases with estimated worldwide prevalences of about 40 and 350 million, respectively; numbers which are predicted to rise even further in the near future due to population ageing. These diseases are also among the top 10 leading causes of disability in high-income countries. By elucidating the genetics and pathogenesis of these disorders further, our results thus could potentially have a large socio-economic impact on the society at large.
Co-expression of polyglutamine disease-associated genes in the human brain (Allen Brain Atlas).