Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae
It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically r...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2014
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| Online Access: | http://hdl.handle.net/1721.1/88059 https://orcid.org/0000-0002-7250-4107 |
| _version_ | 1826193848418697216 |
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| author | Lowe, Jennifer K. Maller, Julian B. Pe'er, Itsik Neale, Benjamin M. Salit, Jacqueline Kenny, Eimear E. Shea, Jessica L. Burkhardt, Ralph Smith, J. Gustav Ji, Weizhen Noel, Martha Foo, Jia Nee Blundell, Maude L. Skilling, Vita Garcia, Laura Sullivan, Marcia L. Lee, Heather E. Labek, Anna Ferdowsian, Hope Auerbach, Steven B. Lifton, Richard P. Newton-Cheh, Christopher Breslow, Jan L. Stoffel, Markus Daly, Mark J. Altshuler, David Friedman, Jeffrey M. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Lowe, Jennifer K. Maller, Julian B. Pe'er, Itsik Neale, Benjamin M. Salit, Jacqueline Kenny, Eimear E. Shea, Jessica L. Burkhardt, Ralph Smith, J. Gustav Ji, Weizhen Noel, Martha Foo, Jia Nee Blundell, Maude L. Skilling, Vita Garcia, Laura Sullivan, Marcia L. Lee, Heather E. Labek, Anna Ferdowsian, Hope Auerbach, Steven B. Lifton, Richard P. Newton-Cheh, Christopher Breslow, Jan L. Stoffel, Markus Daly, Mark J. Altshuler, David Friedman, Jeffrey M. |
| author_sort | Lowe, Jennifer K. |
| collection | MIT |
| description | It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining ≥5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment. |
| first_indexed | 2024-09-23T09:46:20Z |
| format | Article |
| id | mit-1721.1/88059 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:46:20Z |
| publishDate | 2014 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/880592022-09-30T16:41:51Z Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae Lowe, Jennifer K. Maller, Julian B. Pe'er, Itsik Neale, Benjamin M. Salit, Jacqueline Kenny, Eimear E. Shea, Jessica L. Burkhardt, Ralph Smith, J. Gustav Ji, Weizhen Noel, Martha Foo, Jia Nee Blundell, Maude L. Skilling, Vita Garcia, Laura Sullivan, Marcia L. Lee, Heather E. Labek, Anna Ferdowsian, Hope Auerbach, Steven B. Lifton, Richard P. Newton-Cheh, Christopher Breslow, Jan L. Stoffel, Markus Daly, Mark J. Altshuler, David Friedman, Jeffrey M. Massachusetts Institute of Technology. Department of Biology Altshuler, David It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining ≥5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment. Starr Foundation Howard Hughes Medical Institute Deutsche Forschungsgemeinschaft (DFG Bu2263/1-1) National Institutes of Health (U.S.) (1F32DK070527) National Institutes of Health (U.S.) (5 U54 CA121852) Massachusetts Biomedical Research Corporation (Tosteson Postdoctoral Fellowship) National Institutes of Health (U.S.) (NIH/NIDDK grant (5R01 DK60089)) 2014-06-23T15:24:01Z 2014-06-23T15:24:01Z 2009-02 2008-09 Article http://purl.org/eprint/type/JournalArticle 1553-7404 http://hdl.handle.net/1721.1/88059 Lowe, Jennifer K., Julian B. Maller, Itsik Pe’er, Benjamin M. Neale, Jacqueline Salit, Eimear E. Kenny, Jessica L. Shea, et al. “Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae.” Edited by Greg Gibson. PLoS Genet 5, no. 2 (February 6, 2009): e1000365. https://orcid.org/0000-0002-7250-4107 en_US http://dx.doi.org/10.1371/journal.pgen.1000365 PLoS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science Public Library of Science |
| spellingShingle | Lowe, Jennifer K. Maller, Julian B. Pe'er, Itsik Neale, Benjamin M. Salit, Jacqueline Kenny, Eimear E. Shea, Jessica L. Burkhardt, Ralph Smith, J. Gustav Ji, Weizhen Noel, Martha Foo, Jia Nee Blundell, Maude L. Skilling, Vita Garcia, Laura Sullivan, Marcia L. Lee, Heather E. Labek, Anna Ferdowsian, Hope Auerbach, Steven B. Lifton, Richard P. Newton-Cheh, Christopher Breslow, Jan L. Stoffel, Markus Daly, Mark J. Altshuler, David Friedman, Jeffrey M. Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae |
| title | Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae |
| title_full | Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae |
| title_fullStr | Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae |
| title_full_unstemmed | Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae |
| title_short | Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae |
| title_sort | genome wide association studies in an isolated founder population from the pacific island of kosrae |
| url | http://hdl.handle.net/1721.1/88059 https://orcid.org/0000-0002-7250-4107 |
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