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Genome-Wide Association Studies in the Partial Epilepsies CLÁUDIA José Franco Bacanh

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GENETIC STUDIES OF THE COMMON EPILEPSIES: genome-wide association studies in the partial epilepsies CLÁUDIA José Franco Bacanhim Santos CATARINO UCL Institute of Neurology Queen Square London WC1N 3BG A thesis for submission to University College London for the degree of Doctor of Philosophy 2013. Abstract This thesis discusses four studies, looking for genetic determinants of common epilepsies: 1) A genome-wide association study (GWAS) of partial epilepsies (PE), which was the first published GWAS in the field of epilepsy (Chapter 4). 2) A GWAS of mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) (Chapter 5). 3) A case series of patients with refractory MTLE, operated and found to have large microdeletions at 16p13.11, 15q11.2 and others (Chapter 6). 4) A clinical, genetic and neuropathologic study of a series of patients with Dravet syndrome (DS), diagnosed as adults, including genotype-phenotype correlation analysis (Chapter 7). The main findings include: 1) The GWAS of PE has not yielded any genome-wide significant association with common genetic variants, possibly because of insufficient power and phenotypical heterogeneity. It is, however, a strong foundation for further studies, illustrating the feasibility of large multicentre GWAS in the epilepsies (Chapter 4). 2) The GWAS of MTLEHS yielded a borderline genome-wide statistically significant association with three common genetic variants close or intronic to the SCN1A gene, especially in MTLEHS with antecedents of childhood febrile seizures (Chapter 5). 3) Large microdeletions at 16p13.11 and others were found in patients with MTLEHS and not only in idiopathic non-lesional epilepsies. Good outcome after resective epilepsy surgery is possible in “typical” MTLEHS even with large microdeletions (Chapter 6). 4) The identification of a cohort of adults with DS, not diagnosed as children, allowed the description of long-term evolution through adulthood and recognition of clinical features shared later in the evolution. Over sixty percent had SCN1A mutations. Missense mutations were more frequent in patients who survived through adulthood, with truncating mutations and large deletions only found in those who died in early childhood. Medication changes after diagnosis led in some cases to better seizure control, cognition and quality of life. Further evidence for DS as encephalopathy came from post mortem histopathology, with no neuronal loss found in cerebral cortex or hippocampus. 3 Table of contents Declaration ...................................................................................................................................2 Abstract .........................................................................................................................................3 Table of contents ..........................................................................................................................4 List of tables and figures .............................................................................................................9 List of Abbreviations .................................................................................................................16 Acknowledgments ......................................................................................................................21 1 Chapter Introduction ..............................................................................................................24 1.1 Epilepsies – Clinical epidemiology .......................................................................... 24 1.1.1 Incidence and prevalence of epilepsy 24 1.1.2 Burden of epilepsy and mortality 25 1.1.3 Definition of epilepsy and epileptic seizure 25 1.1.4 Classification of the epilepsies and epilepsy syndromes 26 1.2 Genetic epidemiology of common, “complex” disorders ........................................ 28 1.2.1 Family-based genetic studies 35 1.2.2 Population-based genetic association studies 38 1.3 Genetic epidemiology of the epilepsies ................................................................... 50 1.3.1 Evidence for a genetic contribution in epilepsy 51 1.3.2 Monogenic or mendelian epilepsy syndromes 58 1.3.3 Single gene disorders associated with epilepsy 72 1.3.4 Mitochondrial disorders associated with epilepsy 72 1.3.5 Chromosomal abnormalities associated with epilepsy 72 1.3.6 “Complex” epilepsy syndromes 75 1.4 Genetics of temporal lobe epilepsy .......................................................................... 82 1.4.1 Mesial temporal lobe epilepsy 84 1.4.2 Genetics of sporadic mesial temporal lobe epilepsy 85 1.4.3 Hippocampal sclerosis 86 1.4.4 Genetics of hippocampal sclerosis 90 1.5 Febrile seizures ........................................................................................................ 92 1.5.1 Definition of febrile seizures 92 1.5.2 Epidemiology of febrile seizures 92 1.5.3 Classification of febrile seizures 93 1.5.4 Febrile seizures and subsequent afebrile seizures 93 1.5.5 Genetic studies of febrile seizures 94 1.5.6 Genetic epilepsy with febrile seizures plus 100 1.6 Relationship between MTLE, HS and FS .............................................................. 102 1.6.1 Acute MRI studies in children with prolonged febrile seizures 105 1.6.2 Animal models of febrile seizures and epileptogenesis 106 1.7 Role of SCN1A genetic variation in Neurogenetics ............................................... 108 1.7.1 SCN1A and infantile-onset epileptic encephalopathies 110 1.7.2 SCN1A and other neurological diseases 116 1.7.3 SCN1A mutations in asymptomatic individuals 116 4 2 Chapter Methods 120 2.1 Introduction ...................................................................................................... 120 2.2 Ethics approval and patient consent ....................................................................... 120 2.3 Patient recruitment, inclusion criteria and study cohorts ....................................... 121 2.3.1 Patient recruitment strategy 121 2.3.2 Inclusion criteria 121 2.3.3 Exclusion criteria 122 2.3.4 Study cohorts 122 2.3.5 Control cohorts 123 2.4 Phenotyping and creation of London-EPIGEN database ....................................... 126 2.4.1 Definition and prioritisation of the phenotypes to study 126 2.4.2 Phenotyping 127 2.4.3 Creation of the London-EPIGEN database 129 2.4.4 Phenotyping data from collaborating centres 130 2.5 Laboratory methods ............................................................................................... 132 2.5.1 DNA extraction 132 2.5.2 DNA quantification and standardization 132 2.5.3 DNA storage and transport 132 2.5.4 Genotyping 133 2.6 Data analysis ...................................................................................................... 141 2.6.1 Software used for the data analysis 141 2.6.2 Power calculations 141 2.6.3 Statistical analysis 143 3 Chapter Phenotyping ............................................................................................................155 3.1 Introduction ...................................................................................................... 155 3.1.1 Definition of “phenotype” 156 3.1.2 Ideal properties of phenotype and phenotyping 156 3.1.3 Phenotyping in GWA studies 157 3.2 Phenotyping the epilepsies ..................................................................................... 159 3.2.1 General challenges of phenotyping the epilepsies 159 3.2.2 Classification issues of epilepsies and epilepsy syndromes 160 3.2.3 Febrile seizures 165 3.2.4 Family history of epilepsy and febrile seizures 166 3.3 Methods - Building the London EPIGEN database ............................................... 166 3.3.1 Data included in the database 168 3.4 Results ...................................................................................................... 176 3.4.1 Descriptive statistics 176 3.5 Discussion ...................................................................................................... 180 3.5.1 Limitations 180 3.5.2 Next steps 183 4 Chapter Genome-wide association study of partial epilepsy ............................................185 4.1 Introduction ...................................................................................................... 185 4.2 Methods ...................................................................................................... 186 4.2.1 Ethics 186 4.2.2 Recruitment and inclusion criteria 186 4.2.3 Subjects 187 4.2.4 DNA extraction and genotyping 187 5 4.2.5 Genotype calling and genotyping quality control 188 4.2.6 “Gender” checks and relatedness checks 193 4.2.7 Population ancestry and stratification analysis 193 4.2.8 Association analysis 198 4.2.9 Manual inspection of top associated SNPs 199 4.2.10 Pathway analysis (gene ontology analysis) 199 4.2.11 Power calculations 200 4.3 Results ...................................................................................................... 201 4.3.1 Patients 201 4.3.2 Quality control steps 201 4.3.3 Association analysis 204 4.3.4 Pathway analysis (gene ontology analysis) 210 4.4 Discussion and conclusions ................................................................................... 217 4.4.1 Limitations 218 4.4.2 Next steps 220 5 Chapter Genome-wide association study of mesial temporal lobe epilepsy with hippocampal sclerosis ............................................................................................................221 5.1 Introduction .....................................................................................................
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