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Nicotine Dependece Alma Mater Studiorum – Università di Bologna DOTTORATO DI RICERCA IN Biologia Cellulare e Molecolare Ciclo XXX Settore Concorsuale: 05/I1 Settore Scientifico Disciplinare: BIO/18 GENETICA Investigation of genetic risk variants for nicotine dependence and cluster headache Presentata da: Cinzia Cameli Coordinatore Dottorato Supervisore Prof. Giovanni Capranico Prof.ssa Elena Maestrini Co-supervisore Dott.ssa Elena Bacchelli Esame finale anno 2018 TABLE OF CONTENTS ABSTRACT......................................................................................................................... 4 INTRODUCTION ................................................................................................................ 6 CHAPTER 1 Nicotine dependence ...................................................................................... 6 1.1 Biological mechanisms ............................................................................................................ 6 1.2 Nicotinic acetylcholine receptors ............................................................................................ 8 1.2.1 Protein structure ............................................................................................................. 8 1.2.2 Localization and function of neuronal nAChRs ............................................................. 10 1.2.3 α7 nAChRs ..................................................................................................................... 12 1.3 The genetics of nicotine dependence ................................................................................... 12 1.3.1 Linkage analysis ............................................................................................................. 13 1.3.2 Association studies ........................................................................................................ 15 1.3.2.1 Candidate-gene association studies .......................................................................... 16 1.3.2.2 Genome-wide association studies (GWAS) ............................................................... 19 1.3.2.2.1 Results from GWAS on nicotine dependence ..................................................... 23 1.3.3 Targeted sequencing studies ......................................................................................... 25 1.3.4 CHRNA7 and CHRFAM7A gene ...................................................................................... 26 1.3.4.1 Role of CHRNA7-CHRFAM7A loci in ND ..................................................................... 29 1.4 Treatments for nicotine addiction ........................................................................................ 30 1.4.1 Behavioural counselling................................................................................................. 31 1.4.2 Pharmacological therapy ............................................................................................... 31 CHAPTER 2 Cluster headache ........................................................................................... 34 2.1 Clinical features ..................................................................................................................... 34 2.2 Pathophysiology .................................................................................................................... 35 2.3 The genetics of cluster headache .......................................................................................... 37 2.4 Molecular genetic studies of Cluster headache susceptibility .............................................. 37 2.4.1 Linkage studies .............................................................................................................. 40 2.4.2 Association Studies ........................................................................................................ 40 2.5 Nicotine dependence in Cluster Headache ........................................................................... 42 2.6 CH treatments ....................................................................................................................... 43 MATERIALS AND METHODS ............................................................................................. 45 CHAPTER 3 Materials and methods: Role of 7 nAChR in nicotine dependence ............... 45 i 3.1 ND Study sample ................................................................................................................... 45 3.1.1 Smokers sample............................................................................................................. 45 3.1.2 Controls samples ........................................................................................................... 45 3.2 SNP Genotyping and CNVs detection by Illumina Infinium® PsychArray microarrays .......... 46 3.3 Validation of CHRNA7 CNVs by Real-Time PCR ..................................................................... 49 3.4 Mutation screening of the CHRNA7 proximal promoter....................................................... 51 3.4.1 Primer design ................................................................................................................. 51 3.4.2 Polymerase Chain Reaction (PCR) assay ........................................................................ 51 3.4.3 PCR purification ............................................................................................................. 52 3.4.4 Sanger Sequencing reaction .......................................................................................... 53 3.4.5 Ethanol-EDTA Precipitation of Sequencing Reactions ................................................... 53 3.5 In vitro functional analysis of rs28531779 variant on CHRNA7 promoter activity ............... 54 3.5.1 Plasmid construction and cell transfection ................................................................... 54 3.5.2 Dual-Luciferase assay .................................................................................................... 55 3.6 CHRFAM7A Genotyping using ABI3730 and Gene-mapper v3.0 software ........................... 55 3.6.1 Primer design and PCR assays ....................................................................................... 55 3.6.2 PCR product analysis by ABI PRISM 3730 automatic sequencer .................................. 55 3.6.3 Analysis of CHRFAM7A 2bp polymorphism and CNV by Genemapper v3.0 software 56 3.6.4 Analysis of CHRFAM7A copy number by real time PCR ................................................ 57 3.7 Statistical analysis .................................................................................................................. 58 3.7.1 Study sample analysis .................................................................................................... 58 3.7.2 Quantitative analysis ..................................................................................................... 59 3.7.3 Categorical association analysis .................................................................................... 59 3.7.4 Rare variants analysis .................................................................................................... 59 3.7.5 Luciferase assay ............................................................................................................. 59 CHAPTER 4 Materials and methods: Genetic analysis of cluster headache ....................... 60 4.1 CH study sample .................................................................................................................... 60 4.1.1 Cluster headache sample .............................................................................................. 60 4.1.2 Control sample .............................................................................................................. 60 4.2 SNP Genotyping and quality control procedures .................................................................. 60 4.3 Association analysis ............................................................................................................... 62 4.4 Gene-based association analysis ........................................................................................... 63 4.5 MME mutation screening ...................................................................................................... 63 4.5.1 Primer design and PCR assay ......................................................................................... 63 ii 4.5.2 Sanger Sequencing reaction and sequences precipitation ........................................... 64 AIM AND RATIONALE OF THE PROJECT ............................................................................. 66 CHAPTER 5 ....................................................................................................................... 66 5.1 Role of α7 nAChR in nicotine dependence ............................................................................ 67 5.2 Genetic analysis of cluster headache .................................................................................... 69 RESULTS .......................................................................................................................... 72 CHAPTER 6 Analysis of CHRNA7 and CHRFAM7A in nicotine dependence ......................... 72 6.1 Sample characteristics ........................................................................................................... 72 6.2 CHRNA7 copy number assessment
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