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An Investigation of the Contribution of Centrosomal Genes to Schizophrenia and Cognitive Function

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An Investigation of the Contribution of Centrosomal Genes to Schizophrenia and Cognitive Function Provided by the author(s) and NUI Galway in accordance with publisher policies. Please cite the published version when available. Title An investigation of the contribution of centrosomal genes to schizophrenia and cognitive function Author(s) Flynn, Mairéad Publication Date 2020-03-11 Publisher NUI Galway Item record http://hdl.handle.net/10379/15846 Downloaded 2021-09-25T16:18:14Z Some rights reserved. For more information, please see the item record link above. An investigation of the contribution of centrosomal genes to schizophrenia and cognitive function By Mairéad Flynn, B.Sc. A thesis submitted for the Degree of Doctor of Philosophy to the Discipline of Biochemistry, School of Natural Sciences, National University of Ireland, Galway. Supervisor: Dr Derek Morris Discipline of Biochemistry, School of Natural Sciences, National University of Ireland, Galway Co-Supervisor: Prof Ciaran Morrison Discipline of Biochemistry, School of Natural Sciences, National University of Ireland, Galway August 2019 Table of Contents Table of Contents Table of Contents ............................................................................................................. I Declaration .................................................................................................................... VI Statement of Contribution ......................................................................................... VII Acknowledgements .................................................................................................... VIII List of Figures ................................................................................................................ X List of Tables ............................................................................................................... XII List of Supplementary Tables .................................................................................. XIV List of Abbreviations ................................................................................................. XVI Abstract ...................................................................................................................... XXI 1 Introduction ................................................................................................................. 1 1.1 Schizophrenia .................................................................................................... 1 1.1.1 Overview of schizophrenia .............................................................................. 1 1.1.2 Prevalence and socioeconomic burden ............................................................ 2 1.1.3 Current therapies .............................................................................................. 3 1.1.4 Known schizophrenia aetiology ....................................................................... 4 1.2 Genetic Studies .................................................................................................. 6 1.2.1 Genetic variation in the human genome .......................................................... 6 1.2.2 Linkage disequilibrium .................................................................................... 7 1.2.3 Schizophrenia heritability ................................................................................ 8 1.2.4 Linkage studies ................................................................................................ 8 1.2.5 Candidate gene studies ..................................................................................... 9 1.2.6 Genome-wide association studies .................................................................... 9 1.2.7 CNVs .............................................................................................................. 11 1.2.8 Exome sequencing ......................................................................................... 11 1.3 Cognition .............................................................................................................. 12 1.3.1 Cognitive dysfunction in schizophrenia ......................................................... 12 1.3.2 Schizophrenia and cognitive endophenotypes ............................................... 13 1.3.3 Genetics of cognition ..................................................................................... 16 1.3.4 Genetic overlap between schizophrenia and cognition .................................. 17 1.4 Centrosomes ......................................................................................................... 17 1.4.1 Centrosome structure ..................................................................................... 18 1.4.2 Centrosome functions .................................................................................... 23 1.4.3 Centrosome cycle ........................................................................................... 26 I Table of Contents 1.5 Primary Cilia ......................................................................................................... 31 1.5.1 Primary cilium structure ................................................................................. 31 1.5.2 Functions of the primary cilia ........................................................................ 36 1.5.3 Primary cilia assembly and disassembly ........................................................ 38 1.6 The role of the centrosome/cilia in schizophrenia and cognition ......................... 41 1.7 Project aims .......................................................................................................... 43 2 Materials and Methods ............................................................................................. 44 2.1 Materials ............................................................................................................... 44 2.1.1 Chemicals and solutions ................................................................................. 44 2.1.2 Molecular Biology Reagents .......................................................................... 46 2.1.3 Antibodies ...................................................................................................... 48 2.2 Biological materials and tissue culture reagents ................................................... 50 2.2.1 Bacterial strains .............................................................................................. 50 2.2.2 Tissue culture reagents ................................................................................... 51 2.2.3 Cell lines and culture conditions .................................................................... 51 2.3 Identifying SZ risk genes with centrosomal function ........................................... 52 2.4 Neuropsychological testing of SZ risk SNPs within centrosomal genes .............. 52 2.4.1 Study participants and neuropsychological tests ........................................... 52 2.4.2 Genotyping and statistical analysis ................................................................ 54 2.4.3 Replication ..................................................................................................... 55 2.5 Enrichment Analysis ............................................................................................. 56 2.5.1 GWAS Data ................................................................................................... 56 2.5.2 Gene-set Analysis .......................................................................................... 56 2.5.3 Analysis of gene-sets using rare variant data ................................................. 57 2.6 Cell biology methods ............................................................................................ 58 2.6.1 Cell maintenance and proliferation analysis .................................................. 58 2.6.2 Stable cell line generation .............................................................................. 59 2.6.3 Transient transfections ................................................................................... 59 2.5.5 Serum starvation ............................................................................................ 59 2.6.6 Microscopy methods ...................................................................................... 60 2.7 Protein methods .................................................................................................... 61 2.7.1 Protein extraction and preparation ................................................................. 61 2.7.2 SDS-PAGE ..................................................................................................... 61 2.7.3 Semi-dry transfer ............................................................................................ 62 2.7.4 Immunoblotting technique ............................................................................. 63 II Table of Contents 2.8 Nucleic acid methods ............................................................................................ 63 2.8.1 RNA isolation and cDNA synthesis ............................................................... 63 2.8.2 Genomic DNA extraction .............................................................................. 64 2.8.3 Plasmid DNA prep ......................................................................................... 64 2.8.4 Polymerase Chain Reaction (PCR) ................................................................ 65 2.8.5 Restriction digestion
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