Interrogating the intersection of genetic- and gender-based risk for multiple sclerosis
<p>Multiple sclerosis (MS) has no effective prevention or cure and only limited treat- ment options. Significant progress has been made in finding genetic susceptibility loci, but it is still mostly unclear how genetic variants associated with disease are implicated in MS pathogenesis. Mean...
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| Other Authors: | |
| Format: | Thesis |
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2017
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| _version_ | 1797079529928261632 |
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| author | Byrne, EH |
| author2 | McVean, G |
| author_facet | McVean, G Byrne, EH |
| author_sort | Byrne, EH |
| collection | OXFORD |
| description | <p>Multiple sclerosis (MS) has no effective prevention or cure and only limited treat- ment options. Significant progress has been made in finding genetic susceptibility loci, but it is still mostly unclear how genetic variants associated with disease are implicated in MS pathogenesis. Meanwhile, epidemiologically, it has long been clear that women get MS two or three times more frequently than men do. It is also known that there is substantial sexual dimorphism in immune regulation. The analysis presented here attempts to triangulate genetic and sex-based risk for MS, first, in order to understand quantitatively the relationship between sex and genetic risk and, second, to highlight particular genes implicated by both genetics and gender in MS etiology. First, I use a Bayesian framework to assess the relationship between male and female effect sizes at variants previously shown to be associated with MS. I show that the effect size of genetic variants for MS risk is systematically lower in females than males, with female effect size esti- mated at 0.42 times male effect size. Second, I use genome-wide RNAseq data to characterize differential transcription between the sexes, finding over 5000 genes to be differentially expressed, but I do not find sexual dimorphism in cis-eQTL effect sizes. I highlight a subset of genes whose expression is affected by an MS risk variant and whose expression is sexually dimorphic. Several of these genes have functions consistent with complicity in MS. Together, these analyses demon- strate methodology to integrate genetic and genomic data in the context of sexual dimorphism in order to explore the mechanism of disease.</p> |
| first_indexed | 2024-03-07T00:47:13Z |
| format | Thesis |
| id | oxford-uuid:851d0065-4fd2-4276-87b5-738904cf78a5 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T00:47:13Z |
| publishDate | 2017 |
| record_format | dspace |
| spelling | oxford-uuid:851d0065-4fd2-4276-87b5-738904cf78a52022-03-26T21:55:14ZInterrogating the intersection of genetic- and gender-based risk for multiple sclerosisThesishttp://purl.org/coar/resource_type/c_bdccuuid:851d0065-4fd2-4276-87b5-738904cf78a5ORA Deposit2017Byrne, EHMcVean, G<p>Multiple sclerosis (MS) has no effective prevention or cure and only limited treat- ment options. Significant progress has been made in finding genetic susceptibility loci, but it is still mostly unclear how genetic variants associated with disease are implicated in MS pathogenesis. Meanwhile, epidemiologically, it has long been clear that women get MS two or three times more frequently than men do. It is also known that there is substantial sexual dimorphism in immune regulation. The analysis presented here attempts to triangulate genetic and sex-based risk for MS, first, in order to understand quantitatively the relationship between sex and genetic risk and, second, to highlight particular genes implicated by both genetics and gender in MS etiology. First, I use a Bayesian framework to assess the relationship between male and female effect sizes at variants previously shown to be associated with MS. I show that the effect size of genetic variants for MS risk is systematically lower in females than males, with female effect size esti- mated at 0.42 times male effect size. Second, I use genome-wide RNAseq data to characterize differential transcription between the sexes, finding over 5000 genes to be differentially expressed, but I do not find sexual dimorphism in cis-eQTL effect sizes. I highlight a subset of genes whose expression is affected by an MS risk variant and whose expression is sexually dimorphic. Several of these genes have functions consistent with complicity in MS. Together, these analyses demon- strate methodology to integrate genetic and genomic data in the context of sexual dimorphism in order to explore the mechanism of disease.</p> |
| spellingShingle | Byrne, EH Interrogating the intersection of genetic- and gender-based risk for multiple sclerosis |
| title | Interrogating the intersection of genetic- and gender-based risk for multiple sclerosis |
| title_full | Interrogating the intersection of genetic- and gender-based risk for multiple sclerosis |
| title_fullStr | Interrogating the intersection of genetic- and gender-based risk for multiple sclerosis |
| title_full_unstemmed | Interrogating the intersection of genetic- and gender-based risk for multiple sclerosis |
| title_short | Interrogating the intersection of genetic- and gender-based risk for multiple sclerosis |
| title_sort | interrogating the intersection of genetic and gender based risk for multiple sclerosis |
| work_keys_str_mv | AT byrneeh interrogatingtheintersectionofgeneticandgenderbasedriskformultiplesclerosis |