........................................................................................................................................... ii Acknowledgements.......................................................................................................................... v List of Tables .................................................................................................................................. xii List of Figures .................................................................................................................................xiii Chapter 1 : Introduction .................................................................................................................. 1 Schizophrenia ............................................................................................................................... 1 Neuregulin 3 as a SZ susceptibility gene ...................................................................................... 2 Thesis Statement ......................................................................................................................... 3 Contributions ............................................................................................................................... 3 Chapter 2 : Identification and functional studies of regulatory variants in NRG3 associated with a delusion phenotype in schizophrenia .............................................................................................. 5 Abstract ........................................................................................................................................ 5 Introduction ................................................................................................................................. 6 Materials and Methods ................................................................................................................ 7 Nomenclature of NRG3 gene ................................................................................................... 7 Subject Ascertainment and Factor Analysis ............................................................................. 7 Next-generation sequencing, analysis parameters and software ........................................... 8 Deletion studies ....................................................................................................................... 9 Reporter constructs ............................................................................................................... 10 Dual-luciferase reporter assays............................................................................................. 12 Human brain mRNA studies ................................................................................................... 13 Results and Discussion ............................................................................................................... 14 Sequencing of the NRG3 5’ 162kb LD block ........................................................................... 15 A microdeletion upstream of NRG3 is associated with delusions but lacks functional consequences......................................................................................................................... 15 Identification of variation in cis with the microdeletion ....................................................... 16 Variants in intronic regions of NRG3 affect NRG3 expression in vitro and ex-vivo ............... 18 SNPs in NRG3 correlated with alternate first exon use ......................................................... 19 Conclusion .................................................................................................................................. 21 Chapter 3 : Identification of transcription factors binding regulatory regions in NRG3 ............... 34