Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.571702
Title: Exploring associations between the nicotinic acetylcholine receptor gene cluster CHRNA5-A3-B4 and smoking-related behaviours
Author: Ware, Jennifer J.
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2012
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Abstract:
Tobacco use is the leading preventable cause of death worldwide. In order to address this epidemic, it is important that we have a thorough understanding of the aetiology of tobacco use and dependence. Twin and adoption studies have consistently demonstrated the importance of genetic factors in smoking behaviours. The advent of genome-wide technologies has greatly facilitated the search to determine which specific genetic factors contribute to tobacco use phenotypes. A locus within the nicotinic acetylcholine receptor gene cluster CHRNA5-A3-B4 has generated particular interest – that marked by variants rs16969968 in CHRNA5 and rs1051730 in CHRNA3. The primary aim of this thesis was to determine the role played by this locus in smoking-related behaviours, with an emphasis on phenotype refinement. A number of different approaches were utilised to address this objective, namely systematic review and meta-analysis, genetic epidemiology (including detailed phenotyping of smoking behaviour in adolescence), laboratory-based techniques, and genome-wide meta-analysis. Compelling evidence for a small, robust association was observed between the rs1051730/rs16966968 variants and daily cigarette consumption, equivalent to a per allele effect of approximately one cigarette per day. This effect was consistent across population sub-groups. Compelling evidence for an association between this locus and level of tobacco exposure was further illustrated through genome-wide meta-analysis of cotinine levels in current smokers. No association was observed between this locus and smoking initiation however, as examined in a prospectively assessed cohort using precisely defined phenotypes. An association between rs1051730/rs16969968 and smoking topography has yet to be explored. However, a full protocol was developed and piloted to investigate this. In addition, this research has also illustrated the importance of precise, objective, phenotype definition, an observation which has important implications for the fields of molecular genetics and epidemiology.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.571702  DOI: Not available
Keywords: QH426 Genetics ; R Medicine (General)
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