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Elucidating the genetic aetiology of Bipolar Disorder
Introduction: Bipolar disorder (BD) is a debilitating mood disorder with substantial genetic contributions. However, while the existence of its heritability is well-established, the precise genetic components and mechanisms of BD remain unknown. This is a pilot study aimed at optimising the use of s...
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| Format: | Thesis |
| Language: | English |
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Division of Human Genetics
2022
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| _version_ | 1867613317726470144 |
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| access_status_str | Open Access |
| author | Engelbrecht, Hannah-Ruth |
| author2 | Ramesar, Rajkumar |
| author_browse | Engelbrecht, Hannah-Ruth Ramesar, Rajkumar |
| author_facet | Ramesar, Rajkumar Engelbrecht, Hannah-Ruth |
| author_sort | Engelbrecht, Hannah-Ruth |
| collection | Thesis |
| description | Introduction: Bipolar disorder (BD) is a debilitating mood disorder with substantial genetic contributions. However, while the existence of its heritability is well-established, the precise genetic components and mechanisms of BD remain unknown. This is a pilot study aimed at optimising the use of small-scale next generation sequencing (NGS) of family members affected with BD and extending the finding of variants to larger scale association studies, and an attempt at replicating associations from a large genome-wide association study. Methods and Materials: This thesis describes the pathway analysis of whole-genome sequencing (WGS) data from four Afrikaner individuals to identify candidate variants for genotyping in a Family-Based Association Test (FBAT) of 621 individuals of Caucasian and Mixed Ancestry families from South Africa. This was followed by whole-exome sequencing (WES) of eight members of an Afrikaner family to identify rare, coding variation. These two approaches were used to identify both common and rare variation which may be involved in BD. Results: FBAT indicated that variants in the genes ACTN2 (rs4659702) and ANK3 (rs10994318) are associated with BD in a combined group of both Mixed Ancestry and Caucasian individuals, p = 0.0339 and 0.0443, respectively. Furthermore, this study identified a variant in ACTN2 (rs11355106) which was associated with a broad psychiatric phenotype in Mixed Ancestry families (p = 0.0083). WES revealed 168 exomic variants that were shared by five affected members of the family, one of which was rs142375896, a rare and potentially damaging missense variant in SLC26A9. Conclusions: Pathway analysis of both WGS and WES data implicated that the burden of variation in affected individuals lies in regulatory networks, including the regulation of the actin cytoskeleton and circadian entrainment pathways. The association of ANK3 (rs10994318) with BD in a European ancestry cohort was replicated in a South African cohort comprising of Caucasian and Mixed Ancestry individuals, indicating that some risk variants for the disorder could be shared across populations. This thesis confirms the validity of relatively small-scale family-based studies for the study of complex disorders. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/36751 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:34:14.045Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | Division of Human Genetics |
| publisherStr | Division of Human Genetics |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/36751 Elucidating the genetic aetiology of Bipolar Disorder Engelbrecht, Hannah-Ruth Ramesar, Rajkumar Dalvie, Shareefa Medicine Introduction: Bipolar disorder (BD) is a debilitating mood disorder with substantial genetic contributions. However, while the existence of its heritability is well-established, the precise genetic components and mechanisms of BD remain unknown. This is a pilot study aimed at optimising the use of small-scale next generation sequencing (NGS) of family members affected with BD and extending the finding of variants to larger scale association studies, and an attempt at replicating associations from a large genome-wide association study. Methods and Materials: This thesis describes the pathway analysis of whole-genome sequencing (WGS) data from four Afrikaner individuals to identify candidate variants for genotyping in a Family-Based Association Test (FBAT) of 621 individuals of Caucasian and Mixed Ancestry families from South Africa. This was followed by whole-exome sequencing (WES) of eight members of an Afrikaner family to identify rare, coding variation. These two approaches were used to identify both common and rare variation which may be involved in BD. Results: FBAT indicated that variants in the genes ACTN2 (rs4659702) and ANK3 (rs10994318) are associated with BD in a combined group of both Mixed Ancestry and Caucasian individuals, p = 0.0339 and 0.0443, respectively. Furthermore, this study identified a variant in ACTN2 (rs11355106) which was associated with a broad psychiatric phenotype in Mixed Ancestry families (p = 0.0083). WES revealed 168 exomic variants that were shared by five affected members of the family, one of which was rs142375896, a rare and potentially damaging missense variant in SLC26A9. Conclusions: Pathway analysis of both WGS and WES data implicated that the burden of variation in affected individuals lies in regulatory networks, including the regulation of the actin cytoskeleton and circadian entrainment pathways. The association of ANK3 (rs10994318) with BD in a European ancestry cohort was replicated in a South African cohort comprising of Caucasian and Mixed Ancestry individuals, indicating that some risk variants for the disorder could be shared across populations. This thesis confirms the validity of relatively small-scale family-based studies for the study of complex disorders. 2022-08-30T08:03:33Z 2022-08-30T08:03:33Z 2018 2022-07-18T09:19:59Z Master Thesis Masters MSc http://hdl.handle.net/11427/36751 eng application/pdf Division of Human Genetics Faculty of Health Sciences |
| spellingShingle | Medicine Engelbrecht, Hannah-Ruth Elucidating the genetic aetiology of Bipolar Disorder |
| thesis_degree_str | Master's |
| title | Elucidating the genetic aetiology of Bipolar Disorder |
| title_full | Elucidating the genetic aetiology of Bipolar Disorder |
| title_fullStr | Elucidating the genetic aetiology of Bipolar Disorder |
| title_full_unstemmed | Elucidating the genetic aetiology of Bipolar Disorder |
| title_short | Elucidating the genetic aetiology of Bipolar Disorder |
| title_sort | elucidating the genetic aetiology of bipolar disorder |
| topic | Medicine |
| url | http://hdl.handle.net/11427/36751 |
| work_keys_str_mv | AT engelbrechthannahruth elucidatingthegeneticaetiologyofbipolardisorder |