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Investigating the Epidemiological and Genetic Overlap Between Obesity and Alcohol Consumption and Addiction

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Investigating the Epidemiological and Genetic Overlap Between Obesity and Alcohol Consumption and Addiction Section of Metabolic Genetics Investigating the epidemiological and genetic overlap between obesity and alcohol consumption and addiction Undersøgelse af det epidemiologiske og genetiske overlap mellem fedme og alkohol indtag og afhængighed M.Sc. thesis by: Malan Johansen - 20072183 Department of Bioscience - Genetics, Ecology and Evolution Denmark Internal supervisor External supervisor Professor Mikkel Heide Schierup Assistant Professor Niels Grarup University of Aarhus University of Copenhagen Department of Bioscience – Genetics, Ecology and Evolution Department of NNF-CBMR, Metabolic Genetics 8000 Aarhus C, Denmark 2100 København Ø, Denmark Submitted: 01.03.2015 PREFACE AND ACKNOWLEDGEMENTS This master thesis is submitted as part of the Master of Science degree in Biology at the faculty of Bioscience, University of Aarhus and represents a collaborative project between the author and The Novo Nordisk Foundation Center for Basic Metabolic Research (NNF-CBMR) – Metabolic Genetics. Experimental work and genetic analyses have been performed in the research group of Assistant Professor and group leader Niels Grarup, MD, PhD, at the NNF-CBMR. I wish to thank my external supervisor Assistant Professor Niels Grarup, MD, PhD for helpful supervision and support and for the opportunity to be part this research group, setting me on an educational and challenging journey, a true privilege. I wish to give a special thanks to my daily supervisor Ehm Astrid Andersson Galijatovic, MSc, PhD for her excellent tutoring and guidance. I am also grateful for useful help and advice from Johanne Marie Justesen, MSc, PhD-student. Furthermore, I would also like to thank all the good people working at The NNF-CBMR, for always being prepared to help out with whatever obstacle I have encountered. I greatly appreciate all the resources made available to me by the section throughout my time there. Finally, I would like to thank my internal supervisor Professor Mikkel Heide Schierup, from the department of Bioscience – Genetics, Ecology and Evolution at the University of Aarhus for help and advice. To my family I offer my greatest thanks for their unconditional love and support. A special thanks to my boyfriend Carsten Abrahamsen for his patience, encouragement and nurture throughout this process. Malan Johansen, March 2015 2 | P a g e ABSTRACT The common complex disorders of obesity and alcohol use disorder (AUD) are recognized as major health problems, due to their associations to a large number of co-morbidities and premature mortality. Complex disorders are characterized by complex inheritance patterns, where both genetic pre-disposition and environmental factors interact, making the identification of susceptibility genes particularly challenging. In recent years, an emerging view has been that obesity and alcohol addiction are consequences of ingestive behaviors gone awry, mainly through shared disruptive brain reward circuitries that mediate food and drug motivated behavior. Hence, the overall aim of this thesis was to investigate the epidemiological relationship between obesity and alcohol consumption and to possibly identify genetic variants conferring risk for both obesity and alcohol consumption/AUD. This thesis included three studies: In the first study (study I), the relationship between obesity and alcohol consumption was investigated. A significant relationship was established between these two phenotypes. Alcohol intake was found to be inversely associated with BMI in women but not significantly in men, while alcohol intake increased central adiposity in both sexes. Light to moderate consumption seemingly protected against overall weight gain. Higher levels of consumption were however a risk factor for central fat deposition. In the second study (study II.A), it was investigated if a genetic overlap could be established between obesity and alcohol consumption. Genome-wide significant variants associating with BMI and WHR were investigated for their cumulative association with alcohol consumption by use of two genetic risk scores, one representing overall obesity (BMI variants) and one representing central obesity (WHR/WC variants). Moreover, it was investigated if an interaction effect between risk scores and alcohol intake in relation to BMI and WHR could be detected. Neither the BMI nor WC/WHR risk scores were found to associate with risk of alcohol consumption in men or in women. Furthermore, no interaction effects were detected between a high genetic load of BMI or WHR/WC associated variants and alcohol consumption in relation to overall or central obesity. The third study (study II.B), similarly to the second, addressed the potential genetic overlap between obesity (BMI, WHR and WC) and alcohol consumption. However, in this study the opposite approach was undertaken. Variants within a gene-network cumulatively associated with AUD were tested for association with obesity by single SNP analyses. Only one SNP rs2727603 within gene CTNND2 was found to be significantly associated with WHR after multiple testing corrections, which could be mediated through preferential fat deposition in the central abdominal area. However, the association could not be replicated in GIANT or in an internal cohort likely making this a spurious association. The lack of significant associations may be ascribed to a too low statistical power to detect effects and larger homogenous sample sizes are thus warranted. 3 | P a g e To summarize, this study contributed to the ongoing exploration and understanding of the possible overlaps between obesity and alcohol consumption/AUD. An epidemiological relationship was established, however, the hypothesis of shared genetic burdens was not corroborated. 4 | P a g e LIST OF ABBRIVATIONS ADH1B Alcohol dehydrogenase 1B PET Positron emission tomography ADH4 Alcohol dehydrogenase 4 POMC Pro-opiomelanocortin AGRP Agouti-related peptide PYY Peptide YY AIM Ancestry informative markers QC Quality control ALDH2 Aldehyde dehydrogenase QQ Quantile-quantile ARC Arcuate nucleus r2 Correlation coefficient AUD Alcohol use disorder RR Relative risk BED Binge eating disorder SNP Single nucleotide polymorphism BMI Body mass index T2D Type 2 diabetes CD-CV Common disease – common variant WC Waist circumference CD-RV Common disease – rare variant WES Whole exome sequencing CHD Coronary heart disease WGS Whole genome sequencing CNS Central nervous system WHO World health organization COMT Catechol-O-methyltransferase WHR Waist-hip-ratio CTNND2 Catenin (cadherin-associated protein), delta CVD Cardiovascular disease DCH Cancer and Health DRD2 Dopamine D2 receptor DSM Diagnostic and Statistical Manual of Mental Disorders DZ Dizigotic twins EEPD1 Endonuclease/ Exonuclease/ Phosphatase Family Domain Containing 1 Ex4 Exendin-4 FFA Free fatty acids FTO Fat mass and obesity associated gene GABA γ-amino butyric acid GABRA2 γ-amino butyric acid receptor A2 GIANT Genetic Investigation of Anthropometric Traits GLP-1 Glucagon-like peptide 1 GLP-1R Glucagon-like peptide 1 receptor GWAS Genome-wide association studies HPIN Human protein-protein interaction networks HR Hazard ratio HWE Hardy-Weinberg equilibrium IBD Identity by descent IBS Identity-by-state LD Linkage disequilibrium LEPR Leptin receptor MAF Minor allele frequency MC4R Melanocortin 4 receptor MDS Multidimensional scaling plots MZ Monozygotic twins OPRM1 Opioid receptor OR Odds ratio PCA Principal component analyses 5 | P a g e TABLE OF CONTENTS INTRODUCTION .......................................................................................................................... 9 AIM .......................................................................................................................................... 12 CHAPTER I – EPIDEMIOLOGY ..................................................................................................... 13 BACKGROUND .......................................................................................................................... 13 OBESITY ................................................................................................................................... 13 Adipose tissue .................................................................................................................................. 14 Etiology of obesity ........................................................................................................................... 15 Appetite regulation .......................................................................................................................... 17 ALKOHOL USE ........................................................................................................................... 20 Alcohol use disorder......................................................................................................................... 21 Etiology of alcohol use disorder ........................................................................................................ 23 OVERLAPS BETWEEN OBESITY AND ALKOHOL USE .................................................................... 24 Etiological relationship between alcohol intake and obesity .............................................................. 24 Shared pathways in alcohol addiction and obesity ............................................................................ 27 STUDY I .................................................................................................................................... 30 THE EFFECT
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