Understanding the Genetics of Substance Use: Novel Phenotypic and Large-Scale Genomic Approaches

Substance abuse is one of the leading causes of morbidity and mortality in both the developing and the developed worlds. For example, approximately 88,000 people die each year from alcohol- related causes and the annual cost to society of alcohol misuse is estimated to be $249,000,000,000. Converging lines of evidence indicate that these behaviors are substantially heritable: twin and adoption studies have found significant genetic effects for initiation, intensity of use, dependence, and abuse for alcohol, tobacco, marijuana, and other drugs. Genome-wide association studies (GWAS) and candidate gene studies have found a number of robust associations between genetic variants and substance use and dependence. Twin studies have found evidence for common genetic liability across drugs and for distinct genetic influences on substance use initiation and on quantity of use and substance dependence after initiation. Chapter 2 of this thesis describes a rare variant GWAS meta-analysis focused primarily on the role of exonic variants in alcohol and smoking behavior. Across 17 contributing studies, most using the Exome Chip, I assembled a total sample size of between 70,847 and 164,142 individuals for five standard phenotypes: cigarettes per day, smoking initiation, pack years, age of smoking initiation, and drinks per week. In this meta-analysis, I performed single variant tests, gene-based burden tests, and tests conditioned on the effects of common variants. I replicated a number of known associations but failed to find any reproducible novel associations. A modest portion of phenotypic variance (1.7-3.6%) was accounted for by all genotyped rare variants. In summary, if rare variants with large effect sizes exist for these traits, they must be substantially more rare than the modestly rare variants genotyped on the Exome Chip. It follows that large sequenced samples will be required to detect their effects. Chapter 3 of this thesis describes a twin study of adolescent substance use development which used smartphone applications and location tracking to measure twins&rsquo; behavior and environmental exposures. Adolescence is a sensitive period for substance use. Individuals who initiate substance use in early adolescence are at higher risk for dependence diagnoses in adulthood than individuals who initiate later in adolescence. Excessive adolescent substance use is also associated with increased risk for accidental and intentional injuries. Genetic and environmental explanations for adolescent substance use have been advanced but few studies have examined specific environmental hypotheses while accounting for genetic confounding. In this chapter, I show that substance use behavior and related variables can be measured accurately and at high frequency by automated remote assessment and monitoring mediated through the participant&rsquo;s smartphone. I found that adolescent substance use and change in use is heritable, including e-cigarette use, a novel result. I used the participants&rsquo; location data to measure the fraction of time they spent at school during the school day and at home at night, measures of delinquent behavior. These variables were not associated with substance use, contradicting previous results. I also found that the physical distance between twins in a twin pair increased with age and increased more quickly for dizygotic twins than for monozygotic twins, a violation of the equal environment assumption of the classic twin model and an indication that location is heritable. In conclusion, digital phenotyping methods can be used to obtain high quality, longitudinal data in a scalable fashion.</p

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6–11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Cortisol and major depressive disorder-translating findings from humans to animal models and back

Major depressive disorder (MDD) is a global problem for which current pharmacotherapies are not completely effective. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has long been associated with MDD; however, the value of assessing cortisol as a biological benchmark of the pathophysiology or treatment of MDD is still debated. In this review, we critically evaluate the relationship between HPA axis dysfunction and cortisol level in relation to MDD subtype, stress, gender and treatment regime, as well as in rodent models. We find that an elevated cortisol response to stress is associated with acute and severe, but not mild or atypical, forms of MDD. Furthermore, the increased incidence of MDD in females is associated with greater cortisol response variability rather than higher baseline levels of cortisol. Despite almost all current MDD treatments influencing cortisol levels, we could find no convincing relationship between cortisol level and therapeutic response in either a clinical or preclinical setting. Thus, we argue that the absolute level of cortisol is unreliable for predicting the efficacy of antidepressant treatment. We propose that future preclinical models should reliably produce exaggerated HPA axis responses to acute or chronic stress a priori, which may, or may not, alter baseline cortisol levels, while also modelling the core symptoms of MDD that can be targeted for reversal. Combining genetic and environmental risk factors in such a model, together with the interrogation of the resultant molecular, cellular, and behavioral changes, promises a new mechanistic understanding of MDD and focused therapeutic strategies

Novel imidazole and ionic liquid-based platforms as media for co2 capture applications

The objective of this extensive research project was to investigate imidazoles as potential solvents for acid gas removal applications. Imidazoles are integral starting materials and neutral analogs for the synthesis and production of imidazolium-based ionic liquids (ILs) and virtually have not been explored as candidates for novel, CO2 capture media. N-functionalized imidazoles also provide a similar platform as seen in ILs as tunable structures that govern physical and chemical properties leading towards lower volatilities, lower viscosities, higher CO2 uptake, etc. Physical properties (including density, viscosity, and gas solubilities) of N-functionalized imidazoles were recorded providing an initial database for comparisons to commercially-available organic solvents and imidazolium-based ILs. These results show that some novel N-functionalized imidazoles contend with common organic solvents for CO2 separations in terms of dynamic processing properties (i.e. viscosity and CO2 uptake). Imidazoles and ILs also provide a non-volatile media in which fugitive emissions and evaporative losses during solvent regeneration are reduced significantly. Chemical simulations and calculations via COSMOtherm software were also employed to rapidly predict thermophysical properties of these imidazoles and ILs, providing a means of screening of such novel solvents to be optimized for CO2 separation processes. In the concluding chapters of this dissertation, continued research with the N-functionalized imidazole platform are noted, including areas of hybrid solvents, multiply-substituted, isomeric compounds, and imidazole-based polymeric media for acid scavenging (CO2, SO2, etc). (Published By University of Alabama Libraries

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6–11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures