Association and interplay of genetic and epigenetic variants in smoking behavior

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Title: Association and interplay of genetic and epigenetic variants in smoking behavior
Author: Gupta, Richa
Contributor: University of Helsinki, Faculty of Medicine, Clinicum, Institute for Molecular Medicine Finland, University of Helsinki Helsinki, Finland
Publisher: Helsingin yliopisto
Date: 2018-04-20
URI: 978-951-51-4135-4
Thesis level: Doctoral dissertation (article-based)
Abstract: Smoking is a major preventable risk factor for global morbidity and mortality and is influenced by both genetic and environmental factors. With the central goal of understanding the links between the complex trait of smoking behavior and genetic as well as epigenetic variation in the genome, this thesis focuses on identifying novel associations and validating the involvement of candidate genes in smoking behavior. An unbiased, hypothesis-free genome-wide scanning approach for association with genetic variants (single nucleotide polymorphisms; SNPs) in study I and epigenetic variants (DNA methylation) in study II were applied utilizing biomarkers of nicotine metabolism and exposure respectively. Taking a hypothesis-driven targeted approach, in study III, the involvement of neuregulin signaling pathway genes in smoking behavior was examined and validated in a phenotypically rich family sample. With the increasing and due emphasis on interpretation of associations identified in non-protein coding parts of the genome, we investigated the regulatory potential of the highlighted variants as well as assessing mediation via epigenetic mechanisms, utilizing in-house data and publicly available multi-omics resources. In study I, utilizing a biomarker for nicotine clearance rate (nicotine metabolite ratio, NMR) in a genome-wide association study (GWAS) meta-analysis, we identified novel association on chromosome 19, represented by three independent loci mapping to or near the main nicotine metabolizing enzyme CYP2A6. We examined the regulatory potential of the SNPs and identified a subset of genome-wide significant SNPs (173 of 719) as methylation quantitative trait loci (meQTLs). Using causal inference test, we observed methylation at one CpG in DLL3 mediates the effect of genotype on NMR. We also constructed a genetic risk score (GRS) with the independent SNPs identified in the GWAS meta-analysis, which explain ~30% variance observed in NMR. As evidenced by clinical trial studies, NMR influences the efficacy of cessation pharmacotherapeutics highlighting the potential value of our findings. In study II, we utilized cotinine, an established biomarker of nicotine exposure, and performed epigenome-wide association study (EWAS) in regular smokers. We identified several novel loci in smoking-related genes, underlining the value of using biological phenotypes. Cotinine levels are influenced by nicotine intake as well as nicotine clearance, we utilized the GRS constructed in study I to account for such confounding, identifying additional novel loci. We further assessed the role of genetic variants in the highlighted genes and identified several cis and trans meQTLs. A handful of these meQTLs were also directly associated with cotinine levels. At these loci, we examined whether DNA methylation is a mediator between the observed association of genotype and cotinine levels and detected mediation at seven CpG sites, implying DNA methylation may be a cause, not a consequence of nicotine exposure, as commonly assumed. Our results point at an interplay between the genome and epigenome while identifying novel nicotine exposure pertinent loci. In study III, we applied a targeted approach to examine the role of the neuregulin signaling pathway (NSP) genes in smoking behavior utilizing a phenotypically rich family sample. Extensive association and joint linkage and linkage disequilibrium analysis of common, low frequency and rare variants in the ten key NSP genes with a wide spectrum of smoking behavior phenotypes revealed significant association with seven of the ten genes. No significant associations were observed with alcohol use phenotypes hinting at NSP’s involvement specifically in smoking instead of addictions in general. Utilizing integrative methods and multi-omics data from an independent population sample and publicly available resources, we show the majority (56 of 66) of highlighted SNPs have regulatory potential. Our results provide evidence for the involvement of the NSP in smoking behavior, a candidate pathway for smoking and comorbid disorders. Key points from this thesis: 1. Biomarkers can be powerful in identifying meaningful associations even with moderate sample sizes in complex behavioral traits. 2. Genetic and epigenetic differences between individuals influence smoking behavior via genes involved in nicotine metabolism, nicotine dependence, and neuronal pathways. 3. DNA methylation is a molecular mechanism mediating the effects of genotype on smoking behavior phenotypes at some loci. 4. Multi-omics data including, but not limited to, genetics, epigenetics, and transcriptomics can immensely aid in assessing the functional consequences of otherwise seemingly non-functional associations identified via genome-wide association studies providing potentially druggable targets for personalized medication.
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