Genetic analysis of bipolar disorder and alcohol use disorder

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dc.contributor.advisorRamesar, Rajkumaren_ZA
dc.contributor.advisorStein, Dan Jen_ZA
dc.contributor.authorDalvie, Shareefaen_ZA
dc.date.accessioned2016-01-26T12:02:58Z
dc.date.available2016-01-26T12:02:58Z
dc.date.issued2015en_ZA
dc.descriptionIncludes bibliographical referencesen_ZA
dc.description.abstractBackground: Mental health disorders represent a major public health problem in most countries around the world. In South Africa, the lifetime prevalence of psychiatric disorders is 30.3%, with substance-use disorders and mood disorders being the second and third most prevalent classes of lifetime disorders, respectively. Bipolar disorder (BD) has a lifetime prevalence of 1.4% and alcohol use disorder (AUD) a lifetime prevalence of 30.3%, and they are frequently comorbid. Both of these disorders have a relatively high heritability, yet the exact genetic basis of each remains unknown. Genetic variants within the hypothalamic-pituitary-adrenal (HPA)-axis and glutamatergic pathways have previously been implicated in both phenotypes. The aim of this project was to investigate the aetiology of BD and AUD, using high-throughput genomic technologies, bioinformatics, brain-imaging and environmental measures. An additional aim was to assess the genetic aetiology of BD-AUD comorbidity. Methods: For the genetic analysis underlying BD, a South African 'Afrikaner' family was investigated. Whole-genome sequencing (WGS) and whole-genome linkage analysis was performed for individuals with BD Type I (BDI) and unaffected family members using the Illumina HiSeq2000 and Affymetrix Axiom TM Genome-wide CEU 1 Array, respectively. For the AUD analysis, two groups were investigated; a South African adolescent group comprising 80 individuals with AUD and 80 controls, and a group of 8123 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. The South African group of adolescents were genotyped using the Illumina Infinium iSelect custom 6000 BeadChip, childhood trauma data was obtained and brain magnetic resonance images were collected for a subset of this group. Genotype data on HPA-axis genes were obtained from a previous study for the ALSPAC cohort. The fourth group of individuals investigated in this thesis comprised 233 individuals with BD-AUD comorbidity from the Systemic Treatment Enhancement Program for BD (STEP-BD). Genotype data for genes from the glutamatergic and HPA-axis pathways were obtained from a previous study conducted on these individuals. Results: The chromosomal regions 6p25, 10p14-10p15.1, 11q23-11q25, and 13q21-22 scored the highest LOD scores for BD and the most over-represented pathway in the affected family members was the T-cell receptor signalling pathway. In the South African adolescent group, circadian rhythm genes were associated with AUD and childhood trauma predicted alcohol use in adolescence. The gene-imaging analysis identified a SNP in the glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GRIN2B) gene as being associated with brain volume in the left orbitofrontal cortex and posterior cingulate. HPA-axis genes did not show an association with AUD and no significant gene x environment interactions were detected for AUD in the ALSPAC cohort. Single variants in the glutamatergic genes and HPA-axis were not associated with BD-AUD comorbidity. However, from the gene-based analysis, the glutamatergic gene PRKCI was associated with BD-AUD comorbidity. Conclusions: It appears that disruption in immune-related genes may contribute to the development of BD in an Afrikaner family. No significant gene x environment interactions were detected for adolescent AUD. The circadian pathway and childhood trauma may play a role in the development of adolescent AUD. Differential brain volume and BD-AUD comorbidity may be characterised by variation in the glutamatergic pathway. These pathways and the interactions between them should be further investigated in BD and AUD.en_ZA
dc.identifier.apacitationDalvie, S. (2015). <i>Genetic analysis of bipolar disorder and alcohol use disorder</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics. Retrieved from http://hdl.handle.net/11427/16560en_ZA
dc.identifier.chicagocitationDalvie, Shareefa. <i>"Genetic analysis of bipolar disorder and alcohol use disorder."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2015. http://hdl.handle.net/11427/16560en_ZA
dc.identifier.citationDalvie, S. 2015. Genetic analysis of bipolar disorder and alcohol use disorder. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Dalvie, Shareefa AB - Background: Mental health disorders represent a major public health problem in most countries around the world. In South Africa, the lifetime prevalence of psychiatric disorders is 30.3%, with substance-use disorders and mood disorders being the second and third most prevalent classes of lifetime disorders, respectively. Bipolar disorder (BD) has a lifetime prevalence of 1.4% and alcohol use disorder (AUD) a lifetime prevalence of 30.3%, and they are frequently comorbid. Both of these disorders have a relatively high heritability, yet the exact genetic basis of each remains unknown. Genetic variants within the hypothalamic-pituitary-adrenal (HPA)-axis and glutamatergic pathways have previously been implicated in both phenotypes. The aim of this project was to investigate the aetiology of BD and AUD, using high-throughput genomic technologies, bioinformatics, brain-imaging and environmental measures. An additional aim was to assess the genetic aetiology of BD-AUD comorbidity. Methods: For the genetic analysis underlying BD, a South African 'Afrikaner' family was investigated. Whole-genome sequencing (WGS) and whole-genome linkage analysis was performed for individuals with BD Type I (BDI) and unaffected family members using the Illumina HiSeq2000 and Affymetrix Axiom TM Genome-wide CEU 1 Array, respectively. For the AUD analysis, two groups were investigated; a South African adolescent group comprising 80 individuals with AUD and 80 controls, and a group of 8123 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. The South African group of adolescents were genotyped using the Illumina Infinium iSelect custom 6000 BeadChip, childhood trauma data was obtained and brain magnetic resonance images were collected for a subset of this group. Genotype data on HPA-axis genes were obtained from a previous study for the ALSPAC cohort. The fourth group of individuals investigated in this thesis comprised 233 individuals with BD-AUD comorbidity from the Systemic Treatment Enhancement Program for BD (STEP-BD). Genotype data for genes from the glutamatergic and HPA-axis pathways were obtained from a previous study conducted on these individuals. Results: The chromosomal regions 6p25, 10p14-10p15.1, 11q23-11q25, and 13q21-22 scored the highest LOD scores for BD and the most over-represented pathway in the affected family members was the T-cell receptor signalling pathway. In the South African adolescent group, circadian rhythm genes were associated with AUD and childhood trauma predicted alcohol use in adolescence. The gene-imaging analysis identified a SNP in the glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GRIN2B) gene as being associated with brain volume in the left orbitofrontal cortex and posterior cingulate. HPA-axis genes did not show an association with AUD and no significant gene x environment interactions were detected for AUD in the ALSPAC cohort. Single variants in the glutamatergic genes and HPA-axis were not associated with BD-AUD comorbidity. However, from the gene-based analysis, the glutamatergic gene PRKCI was associated with BD-AUD comorbidity. Conclusions: It appears that disruption in immune-related genes may contribute to the development of BD in an Afrikaner family. No significant gene x environment interactions were detected for adolescent AUD. The circadian pathway and childhood trauma may play a role in the development of adolescent AUD. Differential brain volume and BD-AUD comorbidity may be characterised by variation in the glutamatergic pathway. These pathways and the interactions between them should be further investigated in BD and AUD. DA - 2015 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - Genetic analysis of bipolar disorder and alcohol use disorder TI - Genetic analysis of bipolar disorder and alcohol use disorder UR - http://hdl.handle.net/11427/16560 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16560
dc.identifier.vancouvercitationDalvie S. Genetic analysis of bipolar disorder and alcohol use disorder. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2015 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/16560en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDivision of Human Geneticsen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherHuman Geneticsen_ZA
dc.titleGenetic analysis of bipolar disorder and alcohol use disorderen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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