[Thesis]. Manchester, UK: The University of Manchester; 2016.
Swallowing is an important physiological function leading to nourishment of the organism,
controlled by complicated interactions between the muscles, the cranial nerves and
multiple brain structures. Swallowing impairments, also called dysphagia are a major
health burden for patients with neurological diseases such as stroke, Parkinsonâ€™s
disease as well as community dwelling elderly individuals. It has been shown that
activation of undamaged swallowing motor cortex compensates for the initial lost swallowing
function in stroke patients. Non-invasive brain stimulation provides a tool to explore
excitability within the areas of the motor cortex responsible for swallowing muscles.
Repetitive transcranial magnetic stimulation (rTMS) is one such technique, with defined
frequency parameters, however the underlying reasons for the heterogeneity is responses
to low (1Hz) and high (5Hz) frequencies is unclear. These physiological interactions
affecting the neurological control of swallowing may be influenced by multiple genes
and proteins. Insights into the molecular basis of swallowing through genetic interactions
could provide a source of information which can be further used in understanding and
treating swallowing impairments. Existing evidence is limited in terms of candidate
proteins, genes and pathways which might drive the neural control of swallowing.The
aim of my doctoral research was to explore genes which might be involved in swallowing
neurophysiology and pathophysiology. My hypothesis is that swallowing due to its complicated
physiology is most likely affected by multiple genes and interactions between genes
and proteins.To study this hypothesis I used two experimentally distinct study designs.
Firstly I explored a number of single nucleotide polymorphisms (SNPs) and potential
candidate genes presented in the existing literature. Then, I performed a SNP- and
gene-based Genome-Wide Association Study (GWAS) of self-reported swallowing impairments
compared with over 500,000 single nucleotide changes. For GWAS I used a group of 555
community dwelling individuals from the Dyne Steel Cohort from the areas of Manchester
and Newcastle. Further research involved replication of selected genes and SNPs from
literature screening and GWAS using two rTMS paradigms on the largest to date cohort
of healthy young volunteers. Forty one volunteers (were assessed for corticobulbar
excitability after single-pulse TMS. Repeated measurements of motor evoked potentials
from the pharynx and the hand were recorded after the interventions of 1Hz and 5Hz
rTMS. The subjectsâ€™ individual responses were grouped according to multiple criteria
and then associated with factors such as gender, ethnicity, time of day of the stimulation
and individual genetic information.GWAS analysis for association with swallowing impairment
identified one SNP rs17601696 which achieved genome-wide significance (P-value=5Ă—10(-8))
within a non-coding region of chromosome 10. Gene-based analysis did not result in
any genome-wide significant association. In replication of these findings and following
a priori selected genes from the literature (BDNF, COMT, TRKB, APOE, DRD2, GRIN2B
and GRIN1) from neurophysiological studies applying TMS, two main conclusions were
formed. Firstly, rTMS paradigms showed high variability in responses which made the
phenotype more complicated. Secondly the result from GWAS could not be confirmed.
By contrast, SNP rs6269 from the COMT gene was associated with responsiveness of the
pharyngeal MEPs after delivering 1Hz paradigm and rs1800497 from the DRD2 gene with
responsiveness after 5Hz rTMS.Lack of replication of the findings between two experiments
might be caused by high variability in responsiveness with complex molecular networks
of swallowing control where multiple genes with small genetic effects are involved.
Although our findings support the hypothesis that molecular markers can be associated
with swallowing, more studies are needed to understand the individual factors that
determine responsiveness and effectiveness of treatment therapies of swallowing impairments.