Lydall, Gregory John;
(2019)
Genetic Association Studies of Alcohol Dependence.
Doctoral thesis (M.D(Res)), UCL (University College London).
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Abstract
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.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | M.D(Res) |
| Title: | Genetic Association Studies of Alcohol Dependence |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. - Some third party copyright material has been removed from this e-thesis. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10077252 |
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