Integrative Prioritization of Genetic Loci for Nicotine Consumption 公开
Ramgiri, Nikhil (Spring 2020)
Abstract
The consumption of nicotine products constitutes a serious public health concern, due to the substance’s addictive properties and its potential to disrupt psychosocial functioning. Evidence from twin and molecular genetics studies strongly suggest that nicotine consumption, as a trait, adhere to a polygenic model. To date, traditional approaches to characterizing the genetics of polygenic traits, such as genome-wide association studies of nicotine/tobacco use disorders, have been limited in their ability to resolve genomic loci that contribute to the liability to misuse. Drug exposure paradigms in animal models provide us with a potentially useful source of cross-species gene expression data; the current study thus attempted to utilize transcriptomic data from nicotine/tobacco exposure studies in model organisms to better capture genetic variance in nicotine consumption in human populations. The following thesis addresses two primary objectives. Firstly, we construct and assess the viability of an integrative framework that leverages functional cross-species data to characterize the genetic underpinnings of nicotine consumption. Secondly, we determine whether regions of the genome localized by cross-species expression data can inform prediction of nicotine-related phenotypes in an independent human target sample. Our findings indicate significant enrichment of co-transcriptionally regulated loci identified via cross-species data; additionally, these loci carried significant predictive utility when applied to an independent human sample. Our research thus puts forth a promising approach towards unraveling polygenic variants involved in the neuro-molecular physiology of nicotine consumption and other drug use phenotypes.
Table of Contents
Introduction ……………………………………………………………………………………...........................................1
Background of Nicotine/Tobacco Dependence ……………………………………………………………..1
Characterizing the Etiology of Nicotine/Tobacco Dependence ………………………………………2
Study Aims …………………………………………………………………………………………………………………….5
Methods ……………………………………………………………………………………..…………………………………………….6
Assembling a Prioritized Subset …………………………………………………………………………………….6
Genome Partitioning and Heritability Estimation ……………………………………….....................7
Mixed Linear Model Association Analysis ………………………………………………………………………8
Polygenic Risk Score Modeling ………………………………………………………………………………………9
Results …………………………………………………………………………………..………………………………………………..11
Estimation of SNP Heritability of Human Nicotine Consumption across Regions-of-Interest …………………………………………………………………………………………………………………………………….11
Proportion of Gene SNPs Observed in UK Biobank MLMA P-value Distribution ……………13
Application of Genomewide Polygenic Effects and Gene Sets in Add Health Replication Sample…………………………………………………………………………………………………………………………14
Discussion …………………………………………………………………………………….............................................16
References ………………………………………………………………………………………………………………………………21
List of Table and Figures References ……………………………………………………………………………………….27
Collection of Tables …………………………………………………………………………………………………………………28
Collection of Figures …………………………………………………………………………........................................34
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