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Joint Ancestry and Association Testing in Admixed Individuals

For samples of admixed individuals, it is possible to test for both ancestry effects via admixture mapping and genotype effects via association mapping. Here, we describe a joint test called BMIX that combines admixture and association statistics at single markers. We first perform high-density admi...

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Autores principales: Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245293/
https://www.ncbi.nlm.nih.gov/pubmed/22216000
http://dx.doi.org/10.1371/journal.pcbi.1002325
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author Shriner, Daniel
Adeyemo, Adebowale
Rotimi, Charles N.
author_facet Shriner, Daniel
Adeyemo, Adebowale
Rotimi, Charles N.
author_sort Shriner, Daniel
collection PubMed
description For samples of admixed individuals, it is possible to test for both ancestry effects via admixture mapping and genotype effects via association mapping. Here, we describe a joint test called BMIX that combines admixture and association statistics at single markers. We first perform high-density admixture mapping using local ancestry. We then perform association mapping using stratified regression, wherein for each marker genotypes are stratified by local ancestry. In both stages, we use generalized linear models, providing the advantage that the joint test can be used with any phenotype distribution with an appropriate link function. To define the alternative densities for admixture mapping and association mapping, we describe a method based on autocorrelation to empirically estimate the testing burdens of admixture mapping and association mapping. We then describe a joint test that uses the posterior probabilities from admixture mapping as prior probabilities for association mapping, capitalizing on the reduced testing burden of admixture mapping relative to association mapping. By simulation, we show that BMIX is potentially orders-of-magnitude more powerful than the MIX score, which is currently the most powerful frequentist joint test. We illustrate the gain in power through analysis of fasting plasma glucose among 922 unrelated, non-diabetic, admixed African Americans from the Howard University Family Study. We detected loci at 1q24 and 6q26 as genome-wide significant via admixture mapping; both loci have been independently reported from linkage analysis. Using the association data, we resolved the 1q24 signal into two regions. One region, upstream of the gene FAM78B, contains three binding sites for the transcription factor PPARG and two binding sites for HNF1A, both previously implicated in the pathology of type 2 diabetes. The fact that both loci showed ancestry effects may provide novel insight into the genetic architecture of fasting plasma glucose in individuals of African ancestry.
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spelling pubmed-32452932012-01-03 Joint Ancestry and Association Testing in Admixed Individuals Shriner, Daniel Adeyemo, Adebowale Rotimi, Charles N. PLoS Comput Biol Research Article For samples of admixed individuals, it is possible to test for both ancestry effects via admixture mapping and genotype effects via association mapping. Here, we describe a joint test called BMIX that combines admixture and association statistics at single markers. We first perform high-density admixture mapping using local ancestry. We then perform association mapping using stratified regression, wherein for each marker genotypes are stratified by local ancestry. In both stages, we use generalized linear models, providing the advantage that the joint test can be used with any phenotype distribution with an appropriate link function. To define the alternative densities for admixture mapping and association mapping, we describe a method based on autocorrelation to empirically estimate the testing burdens of admixture mapping and association mapping. We then describe a joint test that uses the posterior probabilities from admixture mapping as prior probabilities for association mapping, capitalizing on the reduced testing burden of admixture mapping relative to association mapping. By simulation, we show that BMIX is potentially orders-of-magnitude more powerful than the MIX score, which is currently the most powerful frequentist joint test. We illustrate the gain in power through analysis of fasting plasma glucose among 922 unrelated, non-diabetic, admixed African Americans from the Howard University Family Study. We detected loci at 1q24 and 6q26 as genome-wide significant via admixture mapping; both loci have been independently reported from linkage analysis. Using the association data, we resolved the 1q24 signal into two regions. One region, upstream of the gene FAM78B, contains three binding sites for the transcription factor PPARG and two binding sites for HNF1A, both previously implicated in the pathology of type 2 diabetes. The fact that both loci showed ancestry effects may provide novel insight into the genetic architecture of fasting plasma glucose in individuals of African ancestry. Public Library of Science 2011-12-22 /pmc/articles/PMC3245293/ /pubmed/22216000 http://dx.doi.org/10.1371/journal.pcbi.1002325 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Shriner, Daniel
Adeyemo, Adebowale
Rotimi, Charles N.
Joint Ancestry and Association Testing in Admixed Individuals
title Joint Ancestry and Association Testing in Admixed Individuals
title_full Joint Ancestry and Association Testing in Admixed Individuals
title_fullStr Joint Ancestry and Association Testing in Admixed Individuals
title_full_unstemmed Joint Ancestry and Association Testing in Admixed Individuals
title_short Joint Ancestry and Association Testing in Admixed Individuals
title_sort joint ancestry and association testing in admixed individuals
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245293/
https://www.ncbi.nlm.nih.gov/pubmed/22216000
http://dx.doi.org/10.1371/journal.pcbi.1002325
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