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Title: Genetic association studies of alcohol dependence
Author: Lydall, Gregory John
ISNI:       0000 0004 7970 6603
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Objectives: Alcohol dependence (AD) commonly co-occurs with bipolar disorder (BP) and schizophrenia (SZ). Together these heritable (and cross-heritable disorders) account for significant morbidity and mortality. The genetic comorbidity between AD, BP, and SZ was investigated to find genetic factors affecting risk for developing AD. Methods: Subjects were from the UCL AD (n=586), BP, and SZ samples and supernormal controls (SNC; up to 603 subjects). The BP and SCZ subjects were further categorized as having comorbid AD (BPALC n=143; SZALC n=77) or without AD comorbidity (BPnonALC n=367; SZnonALC n=384). The following single gene association study or Genome-Wide Association Studies (GWAS) of the above phenotypes were performed: i) Seven SNPs previously associated with AD in the GABRA2 gene were genotyped in the AD cases and SNCs. ii) GWAS of BPALC vs SNC; and BPALC vs BPnonALC. iii) GWAS of SZALC vs SNC; and SZALC vs SZnonALC. iv) Meta-analysis of BPALC and SZALC GWAS data. Single marker tests, and gene-based permutation tests on all SNPs within a 50kb region flanking each gene, were performed. Genes previously implicated with AD and related phenotypes were tested for association in the datasets. Pathways analysis were performed on all genes uncorrected p < 0.01. Results: i) None of the GABRA2 SNPs showed association with AD. ii-iv) No GWAS SNP met the genome-wide significance threshold. Several gene wide tests with CNS genes suggested replication of prior AD findings. AD implicated pathways included neuronal generation; inflammation; reaction to inorganic substance; transportation; and tyrosine metabolism. Conclusions: No significant single marker associations were detected in the AD sample or comorbid AD groups. Potential candidate genes were suggestively implicated by gene-based analysis and literature replication. Possible mechanisms for AD susceptibility genes in affective/psychotic disorders are discussed. This exploratory study was underpowered to detect genome wide significance and larger studies are needed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available