The molecular genetics of bipolar affective disorder : South African populations, endophenotypes, and environmental influence

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dc.contributor.advisorRamesar, Rajen_ZA
dc.contributor.advisorSolms, Marken_ZA
dc.contributor.authorSavitz, Jonathanen_ZA
dc.date.accessioned2014-09-12T07:05:04Z
dc.date.available2014-09-12T07:05:04Z
dc.date.issued2006en_ZA
dc.descriptionIncludes bibliographical references.en_ZA
dc.description.abstractThe identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance that may include by genetic heterogeneity, genetic epistasis, gene-environment interactions, incomplete penetrance and variable expressivity. In this thesis three strategies were employed to ameliorate these confounding factors. The first strategy was to focus on a theoretically genetically-homogeneous population with BPD. A unique South African sample including 190 individuals of the relativity reproductively-isolated Afrikaner population yielded promising evidence of linkage to chromosome 1 q31-32 and weaker peaks at lOq23 and 13q32, regions previously implicated in the disorder. A family-based analysis suggested that the 3' variable number tandem repeat (VNTR) variant of the dopamine transporter gene (DAT) is associated with bipolar-spectrum illness in the 132-strong sample of British ancestry. The second strategy was to carry out genetic linkage and association analyses using quantitative traits (elldophenotypes) that were closely associated with BPD. As part of this process a variety of personality traits were evaluated in the cohort, and anxiety related, novelty-seeking, hyperthymic, and cyclothymic personality traits were found to aggregate in participants with BPD and to a lesser extent repeated unipolar illness (MDE-R). These traits were therefore used as quantitative markers or endophenotypes of BPD. The quantitative linkage analysis indicated that a variant in the region of 13q32 may influence the development of novelty-seeking-related traits in the largest Afrikaner pedigree, while the personality trait, ""Stability"", was weakly linked to 4p16 in the total sample. The catechol-o-methytransferase (COM1) Va1l58Mct and the Brain Derived Neurotrophic Factor (BDNF) Va1l66Met polymorphisms were associated with mood-labile-cyclothymic and hyperthymic·-novelty-seeking traits, respectively. the DA T VNTR and the Notch4 exonic repeat variants were associated with a broad range of ""pathological"" personality traits in the sa11lples of British and Afrikaner origin, respectively. The sample was also evaluated with a battery of neuropsychological tasks and the BPD 1 and MDE-R groups displayed both verbal and visual memory recall deficits while the BPD 1 sample also suffered from recognition memory deficits. The neurocognitive trait, ""Memory"" was therefore used as a second endophenotype generating potential linkage signals on IOq23 and 22q 11. The exonic 48bp VNTR polymorphism in the dopamine 4 receptor (DRD4) gene was associated with '""Memory"" performance. As a third strategy, a potentially important aetiological factor, childhood trauma, was measured, and used to test for gene-environment interactions between the various candidate genes and bipolar-illness or BPD-related endophenotypes in the cohort. BPD and M DE-R individuals displayed significantly higher levels of emotional and physical abuse, and the former variable was also associated with the development of anxiety-related and unstable personality traits. A functional variant of the COM1 gene was found to interact with abuse to predispose to anxiety-related, unstable cyclothymic and novelty-seeking related personality traits. The combination of childhood abuse and possession of low-activity MAO-A gene variants was also associated the development of more anxious and unstable personality traits. All interaction between sexual abuse and the B])NF gene modulated performance on verbal and visual memory tasks. A similar interaction between the ApoE gene and sexual abuse was observed. Although a number of theoretical obstacles remain to be resolved, the analyses of isolated populations coupled with the use of endophenotypes and the testing or gene environment interactions, holds out great promise for the eventual elucidation of the genetic basis of hi polar affective disorder.en_ZA
dc.identifier.apacitationSavitz, J. (2006). <i>The molecular genetics of bipolar affective disorder : South African populations, endophenotypes, and environmental influence</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics. Retrieved from http://hdl.handle.net/11427/7435en_ZA
dc.identifier.chicagocitationSavitz, Jonathan. <i>"The molecular genetics of bipolar affective disorder : South African populations, endophenotypes, and environmental influence."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2006. http://hdl.handle.net/11427/7435en_ZA
dc.identifier.citationSavitz, J. 2006. The molecular genetics of bipolar affective disorder : South African populations, endophenotypes, and environmental influence. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Savitz, Jonathan AB - The identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance that may include by genetic heterogeneity, genetic epistasis, gene-environment interactions, incomplete penetrance and variable expressivity. In this thesis three strategies were employed to ameliorate these confounding factors. The first strategy was to focus on a theoretically genetically-homogeneous population with BPD. A unique South African sample including 190 individuals of the relativity reproductively-isolated Afrikaner population yielded promising evidence of linkage to chromosome 1 q31-32 and weaker peaks at lOq23 and 13q32, regions previously implicated in the disorder. A family-based analysis suggested that the 3' variable number tandem repeat (VNTR) variant of the dopamine transporter gene (DAT) is associated with bipolar-spectrum illness in the 132-strong sample of British ancestry. The second strategy was to carry out genetic linkage and association analyses using quantitative traits (elldophenotypes) that were closely associated with BPD. As part of this process a variety of personality traits were evaluated in the cohort, and anxiety related, novelty-seeking, hyperthymic, and cyclothymic personality traits were found to aggregate in participants with BPD and to a lesser extent repeated unipolar illness (MDE-R). These traits were therefore used as quantitative markers or endophenotypes of BPD. The quantitative linkage analysis indicated that a variant in the region of 13q32 may influence the development of novelty-seeking-related traits in the largest Afrikaner pedigree, while the personality trait, ""Stability"", was weakly linked to 4p16 in the total sample. The catechol-o-methytransferase (COM1) Va1l58Mct and the Brain Derived Neurotrophic Factor (BDNF) Va1l66Met polymorphisms were associated with mood-labile-cyclothymic and hyperthymic·-novelty-seeking traits, respectively. the DA T VNTR and the Notch4 exonic repeat variants were associated with a broad range of ""pathological"" personality traits in the sa11lples of British and Afrikaner origin, respectively. The sample was also evaluated with a battery of neuropsychological tasks and the BPD 1 and MDE-R groups displayed both verbal and visual memory recall deficits while the BPD 1 sample also suffered from recognition memory deficits. The neurocognitive trait, ""Memory"" was therefore used as a second endophenotype generating potential linkage signals on IOq23 and 22q 11. The exonic 48bp VNTR polymorphism in the dopamine 4 receptor (DRD4) gene was associated with '""Memory"" performance. As a third strategy, a potentially important aetiological factor, childhood trauma, was measured, and used to test for gene-environment interactions between the various candidate genes and bipolar-illness or BPD-related endophenotypes in the cohort. BPD and M DE-R individuals displayed significantly higher levels of emotional and physical abuse, and the former variable was also associated with the development of anxiety-related and unstable personality traits. A functional variant of the COM1 gene was found to interact with abuse to predispose to anxiety-related, unstable cyclothymic and novelty-seeking related personality traits. The combination of childhood abuse and possession of low-activity MAO-A gene variants was also associated the development of more anxious and unstable personality traits. All interaction between sexual abuse and the B])NF gene modulated performance on verbal and visual memory tasks. A similar interaction between the ApoE gene and sexual abuse was observed. Although a number of theoretical obstacles remain to be resolved, the analyses of isolated populations coupled with the use of endophenotypes and the testing or gene environment interactions, holds out great promise for the eventual elucidation of the genetic basis of hi polar affective disorder. DA - 2006 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2006 T1 - The molecular genetics of bipolar affective disorder : South African populations, endophenotypes, and environmental influence TI - The molecular genetics of bipolar affective disorder : South African populations, endophenotypes, and environmental influence UR - http://hdl.handle.net/11427/7435 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/7435
dc.identifier.vancouvercitationSavitz J. The molecular genetics of bipolar affective disorder : South African populations, endophenotypes, and environmental influence. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2006 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/7435en_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.titleThe molecular genetics of bipolar affective disorder : South African populations, endophenotypes, and environmental influenceen_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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