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A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic
Resequencing is an emerging tool for identification of rare disease-associated mutations. Rare mutations are difficult to tag with SNP genotyping, as genotyping studies are designed to detect common variants. However, studies have shown that genetic heterogeneity is a probable scenario for common di...
Autores principales: | , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633048/ https://www.ncbi.nlm.nih.gov/pubmed/19214210 http://dx.doi.org/10.1371/journal.pgen.1000384 |
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author | Madsen, Bo Eskerod Browning, Sharon R. |
author_facet | Madsen, Bo Eskerod Browning, Sharon R. |
author_sort | Madsen, Bo Eskerod |
collection | PubMed |
description | Resequencing is an emerging tool for identification of rare disease-associated mutations. Rare mutations are difficult to tag with SNP genotyping, as genotyping studies are designed to detect common variants. However, studies have shown that genetic heterogeneity is a probable scenario for common diseases, in which multiple rare mutations together explain a large proportion of the genetic basis for the disease. Thus, we propose a weighted-sum method to jointly analyse a group of mutations in order to test for groupwise association with disease status. For example, such a group of mutations may result from resequencing a gene. We compare the proposed weighted-sum method to alternative methods and show that it is powerful for identifying disease-associated genes, both on simulated and Encode data. Using the weighted-sum method, a resequencing study can identify a disease-associated gene with an overall population attributable risk (PAR) of 2%, even when each individual mutation has much lower PAR, using 1,000 to 7,000 affected and unaffected individuals, depending on the underlying genetic model. This study thus demonstrates that resequencing studies can identify important genetic associations, provided that specialised analysis methods, such as the weighted-sum method, are used. |
format | Text |
id | pubmed-2633048 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-26330482009-02-13 A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic Madsen, Bo Eskerod Browning, Sharon R. PLoS Genet Research Article Resequencing is an emerging tool for identification of rare disease-associated mutations. Rare mutations are difficult to tag with SNP genotyping, as genotyping studies are designed to detect common variants. However, studies have shown that genetic heterogeneity is a probable scenario for common diseases, in which multiple rare mutations together explain a large proportion of the genetic basis for the disease. Thus, we propose a weighted-sum method to jointly analyse a group of mutations in order to test for groupwise association with disease status. For example, such a group of mutations may result from resequencing a gene. We compare the proposed weighted-sum method to alternative methods and show that it is powerful for identifying disease-associated genes, both on simulated and Encode data. Using the weighted-sum method, a resequencing study can identify a disease-associated gene with an overall population attributable risk (PAR) of 2%, even when each individual mutation has much lower PAR, using 1,000 to 7,000 affected and unaffected individuals, depending on the underlying genetic model. This study thus demonstrates that resequencing studies can identify important genetic associations, provided that specialised analysis methods, such as the weighted-sum method, are used. Public Library of Science 2009-02-13 /pmc/articles/PMC2633048/ /pubmed/19214210 http://dx.doi.org/10.1371/journal.pgen.1000384 Text en Madsen, Browning. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Madsen, Bo Eskerod Browning, Sharon R. A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic |
title | A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic |
title_full | A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic |
title_fullStr | A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic |
title_full_unstemmed | A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic |
title_short | A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic |
title_sort | groupwise association test for rare mutations using a weighted sum statistic |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633048/ https://www.ncbi.nlm.nih.gov/pubmed/19214210 http://dx.doi.org/10.1371/journal.pgen.1000384 |
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