Alcohol dependence and associated disease: determinants, pathogenesis and treatment

Alcohol is an agent used in many societies, but the context of use can greatly differ. Due to the toxic properties of alcohol, the negative effects can vary from intoxication to alcohol dependence and alcohol-related disease. The cost associated with these consequences is estimated to be £21 billion per annum in the UK alone. Moreover, alcohol disproportionately influences those under the age of 65, and is considered the third leading cause of non-communicable disease by the World Health Organisation.

Alongside social and productivity consequences, alcohol is implicated in the development and progression of many disease states. The work proposed for this Fellowship will focus on alcohol dependence itself and alcohol's consequences in the setting of liver disease and brain injury. The work in each of these areas is summarised below.

Alcohol dependence/consumption:

This project will use quantitative analysis to explore genetic variants and biological measurements collected by UK Biobank and their association with a) alcohol consumption status (teetotal vs. very heavy drinking), and b) alcohol consumption as a continuous variable. We will attempt to replicate findings in other national/international Biobanks or as part of collaborative work with other groups that have collected samples from similar people. At the same time as attempting to replicate findings, any identified genes will be further investigated using both computational and laboratory techniques using model organisms. The ultimate aim of this work is to understand the true value of the findings from the UK Biobank work. It is hoped that this work will lead to the identification of one or several markers that can be used to develop new anti-craving treatments for alcohol in the future. Furthermore, longitudinal follow-up in UK Biobank will be used to assess association between alcohol consumption and later disease development and progression and (cause of) death.


Alcohol-related liver disease:
Liver disease is common in people that have alcohol use disorders. However, not all people that drink heavily develop alcohol-related liver disease. This project within the fellowship aims to identify early markers of disease onset/progression. UK Biobank will be the first data source to be used. The initial stages of this work will be to confirm the diagnosis of alcohol-related liver disease using electronic health records from primary and secondary care. The genetic, non-genetic and liver scan information available about the individuals will then be used to explore common factors found in those with a confirmed diagnosis. Subsequent replication of any findings will then be attempted in a laboratory setting using laboratory models and/or biological samples from GenomALC (http://www.genomalc.org/; named Fellow a member of the Consortium).


Alcohol-related brain injury:
Alcohol Related Brain Injury (ARBI) is an umbrella term for a number of neuropsychiatric conditions caused by heavy drinking. It is under-detected and under-treated in current healthcare systems, but its impact on the patient and their ability to adhere to treatment packages is beginning to be appreciated. This project will use UK Biobank brain scan data to delineate the consequences of heavy alcohol consumption on brain structure and function. Linking genetic and imaging data will enable the association between genes identified in the alcohol dependence/consumption work and different brain structures to be explored. The aim of this project is to create computational and/or laboratory models of alcohol-related brain injury. It would then be a future aim to work with clinical colleagues to develop therapeutic interventions for ARBI.

Our understanding of the biological mechanisms underpinning alcohol consumption and related disease onset/progression is poor. The combination of detailed phenotypic and genetic data available via UK Biobank provides the ideal opportunity to investigate specific factors associated with alcohol consumption. Traditional epidemiological methods will be used alongside GWAS (Linear mixed model approach), Mendelian randomisation and Phenome-wide association studies to examine the interplay between disease phenotypes, the causal effect of modifiable exposures on disease, and regions of genetic interest. Genetic engineering in C. elegans will be employed to understand how genes identified through UK Biobank data analysis influence alcohol consumption and metabolism. The ultimate aim is to identify novel drug targets or pathways that may be suitable for new drug discovery or drug repurposing.

Theoretical and empirical observations suggest that a given level of alcohol does not impact each individual equally, with some not developing clinically significant alcohol-related organ disease and those that do, develop different target organ disease. This programme of work will investigate alcohol-related liver disease and alcohol-related brain injury.

Alcohol-related liver disease:
First, confirm phenotypes using primary and secondary electronic health records in UK Biobank. Second, explore phenotypic and genetic traits in cases and drinking/non-drinking controls with the aim to identify early biomarkers. Third, replicate in model organisms and well-defined human samples.

Alcohol-related brain injury:
Use UK Biobank brain MRI data to delineate the consequences of heavy alcohol consumption on brain structure and function. Linking genetic and imaging data will enable the association between robust SNPs or other genetic variants and brain phenotypes to be explored. The aim is to create computational and/or organism-based models of alcohol-related brain injury.