A genome-wide scan in forty large pedigrees with multiple sclerosis.
The epidemiology of multiple sclerosis suggests that a complex interaction of genes and environment contribute to susceptibility. To enrich for families with large genetic effects and to potentially reduce genetic heterogeneity, we screened a sample of 18,794 probands and identified forty families w...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2007
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| _version_ | 1826275301301157888 |
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| author | Willer, C Dyment, D Cherny, S Ramagopalan, S Herrera, B Morrison, K Sadovnick, A Risch, N Ebers, G |
| author_facet | Willer, C Dyment, D Cherny, S Ramagopalan, S Herrera, B Morrison, K Sadovnick, A Risch, N Ebers, G |
| author_sort | Willer, C |
| collection | OXFORD |
| description | The epidemiology of multiple sclerosis suggests that a complex interaction of genes and environment contribute to susceptibility. To enrich for families with large genetic effects and to potentially reduce genetic heterogeneity, we screened a sample of 18,794 probands and identified forty families with four or more affected individuals. Within these 40 families, HLA DRB1*15 was present in 70% of affected individuals; the transmission disequilibrium test showed a significant excess in transmission of DRB1*15 alleles to affected individuals (47 transmitted, 19 untransmitted, chi (2) = 11.9, p = 0.00057). A 10 cM genome scan was performed and analyzed for linkage under a parametric model with heterogeneity. No excess of significant sharing was observed (HLOD > 3.3) in the parametric multipoint analysis. No region exceeded that for marker GATA8A05 with an HLOD = 1.11. Follow-up genotyping with 17 microsatellites revealed a significant two-point parametric HLOD = 3.99 at marker D4S1597. Transmission disequilibrium tests for markers in this candidate region showed no transmission distortion. A scan for variants in a gene adjacent to D4S1597, PALLD, was negative for synonymous or nonsynonymous changes. A final multipoint scan incorporating all microsatellites in the region provided an HLOD = 1.30. The inability to find significant linkage in these highly penetrant families suggests that linkage is not the optimal tool for dissecting the inheritance of MS. |
| first_indexed | 2024-03-06T22:56:37Z |
| format | Journal article |
| id | oxford-uuid:609e333f-0069-40e9-8599-84bde57fdc0b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:56:37Z |
| publishDate | 2007 |
| record_format | dspace |
| spelling | oxford-uuid:609e333f-0069-40e9-8599-84bde57fdc0b2022-03-26T17:54:28ZA genome-wide scan in forty large pedigrees with multiple sclerosis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:609e333f-0069-40e9-8599-84bde57fdc0bEnglishSymplectic Elements at Oxford2007Willer, CDyment, DCherny, SRamagopalan, SHerrera, BMorrison, KSadovnick, ARisch, NEbers, GThe epidemiology of multiple sclerosis suggests that a complex interaction of genes and environment contribute to susceptibility. To enrich for families with large genetic effects and to potentially reduce genetic heterogeneity, we screened a sample of 18,794 probands and identified forty families with four or more affected individuals. Within these 40 families, HLA DRB1*15 was present in 70% of affected individuals; the transmission disequilibrium test showed a significant excess in transmission of DRB1*15 alleles to affected individuals (47 transmitted, 19 untransmitted, chi (2) = 11.9, p = 0.00057). A 10 cM genome scan was performed and analyzed for linkage under a parametric model with heterogeneity. No excess of significant sharing was observed (HLOD > 3.3) in the parametric multipoint analysis. No region exceeded that for marker GATA8A05 with an HLOD = 1.11. Follow-up genotyping with 17 microsatellites revealed a significant two-point parametric HLOD = 3.99 at marker D4S1597. Transmission disequilibrium tests for markers in this candidate region showed no transmission distortion. A scan for variants in a gene adjacent to D4S1597, PALLD, was negative for synonymous or nonsynonymous changes. A final multipoint scan incorporating all microsatellites in the region provided an HLOD = 1.30. The inability to find significant linkage in these highly penetrant families suggests that linkage is not the optimal tool for dissecting the inheritance of MS. |
| spellingShingle | Willer, C Dyment, D Cherny, S Ramagopalan, S Herrera, B Morrison, K Sadovnick, A Risch, N Ebers, G A genome-wide scan in forty large pedigrees with multiple sclerosis. |
| title | A genome-wide scan in forty large pedigrees with multiple sclerosis. |
| title_full | A genome-wide scan in forty large pedigrees with multiple sclerosis. |
| title_fullStr | A genome-wide scan in forty large pedigrees with multiple sclerosis. |
| title_full_unstemmed | A genome-wide scan in forty large pedigrees with multiple sclerosis. |
| title_short | A genome-wide scan in forty large pedigrees with multiple sclerosis. |
| title_sort | genome wide scan in forty large pedigrees with multiple sclerosis |
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