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Vol. 66, No. 2, 2008
Issue release date: March 2008
Free Access
Hum Hered 2008;66:67–86
(DOI:10.1159/000119107)

Review and Evaluation of Methods Correcting for Population Stratification with a Focus on Underlying Statistical Principles

Tiwari H.K.a · Barnholtz-Sloan J.b · Wineinger N.a · Padilla M.A.a · Vaughan L.K.a · Allison D.B.a, b
aDepartment of Biostatistics, Section on Statistical Genetics, and bClinical Nutrition Research Center, University of Alabama at Birmingham, Birmingham, Ala., cCase Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
email Corresponding Author

Abstract

When two or more populations have been separated by geographic or cultural boundaries for many generations, drift, spontaneous mutations, differential selection pressures and other factors may lead to allele frequency differences among populations. If these ‘parental’ populations subsequently come together and begin inter-mating, disequilibrium among linked markers may span a greater genetic distance than it typically does among populations under panmixia [see glossary]. This extended disequilibrium can make association studies highly effective and more economical than disequilibrium mapping in panmictic populations since less marker loci are needed to detect regions of the genome that harbor phenotype-influencing loci. However, under some circumstances, this process of intermating (as well as other processes) can produce disequilibrium between pairs of unlinked loci and thus create the possibility of confounding or spurious associations due to this population stratification. Accordingly, researchers are advised to employ valid statistical tests for linkage disequilibrium mapping allowing conduct of genetic association studies that control for such confounding. Many recent papers have addressed this need. We provide a comprehensive review of advances made in recent years in correcting for population stratification and then evaluate and synthesize these methods based on statistical principles such as (1) randomization, (2) conditioning on sufficient statistics, and (3) identifying whether the method is based on testing the genotype-phenotype covariance (conditional upon familial information) and/or testing departures of the marginal distribution from the expected genotypic frequencies.


 goto top of outline Key Words

  • Admixture
  • Ancestry
  • Association
  • Covariance-based tests
  • Genomic control
  • Linkage
  • Marginal-based tests
  • QTL
  • RAM
  • Randomization
  • SAT
  • Structure
  • Sufficient statistics
  • TDT

 goto top of outline Abstract

When two or more populations have been separated by geographic or cultural boundaries for many generations, drift, spontaneous mutations, differential selection pressures and other factors may lead to allele frequency differences among populations. If these ‘parental’ populations subsequently come together and begin inter-mating, disequilibrium among linked markers may span a greater genetic distance than it typically does among populations under panmixia [see glossary]. This extended disequilibrium can make association studies highly effective and more economical than disequilibrium mapping in panmictic populations since less marker loci are needed to detect regions of the genome that harbor phenotype-influencing loci. However, under some circumstances, this process of intermating (as well as other processes) can produce disequilibrium between pairs of unlinked loci and thus create the possibility of confounding or spurious associations due to this population stratification. Accordingly, researchers are advised to employ valid statistical tests for linkage disequilibrium mapping allowing conduct of genetic association studies that control for such confounding. Many recent papers have addressed this need. We provide a comprehensive review of advances made in recent years in correcting for population stratification and then evaluate and synthesize these methods based on statistical principles such as (1) randomization, (2) conditioning on sufficient statistics, and (3) identifying whether the method is based on testing the genotype-phenotype covariance (conditional upon familial information) and/or testing departures of the marginal distribution from the expected genotypic frequencies.

Copyright © 2008 S. Karger AG, Basel


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 goto top of outline Author Contacts

Hemant K. Tiwari, PhD
Department of Biostatistics, Section on Statistical Genetics
Ryals Public Health Building, 420D, University of Alabama at Birmingham
1665 University Blvd., Birmingham, AL 35294 (USA)
Tel. +1 205 934 4907, Fax +1 205 975 2541, E-Mail htiwari@uab.edu


 goto top of outline Article Information

Published online: March 31, 2008
Number of Print Pages : 20
Number of Figures : 1, Number of Tables : 2, Number of References : 192


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 66, No. 2, Year 2008 (Cover Date: March 2008)

Journal Editor: Devoto M. (Philadelphia, Pa.)
ISSN: 0001–5652 (Print), eISSN: 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

When two or more populations have been separated by geographic or cultural boundaries for many generations, drift, spontaneous mutations, differential selection pressures and other factors may lead to allele frequency differences among populations. If these ‘parental’ populations subsequently come together and begin inter-mating, disequilibrium among linked markers may span a greater genetic distance than it typically does among populations under panmixia [see glossary]. This extended disequilibrium can make association studies highly effective and more economical than disequilibrium mapping in panmictic populations since less marker loci are needed to detect regions of the genome that harbor phenotype-influencing loci. However, under some circumstances, this process of intermating (as well as other processes) can produce disequilibrium between pairs of unlinked loci and thus create the possibility of confounding or spurious associations due to this population stratification. Accordingly, researchers are advised to employ valid statistical tests for linkage disequilibrium mapping allowing conduct of genetic association studies that control for such confounding. Many recent papers have addressed this need. We provide a comprehensive review of advances made in recent years in correcting for population stratification and then evaluate and synthesize these methods based on statistical principles such as (1) randomization, (2) conditioning on sufficient statistics, and (3) identifying whether the method is based on testing the genotype-phenotype covariance (conditional upon familial information) and/or testing departures of the marginal distribution from the expected genotypic frequencies.



 goto top of outline Author Contacts

Hemant K. Tiwari, PhD
Department of Biostatistics, Section on Statistical Genetics
Ryals Public Health Building, 420D, University of Alabama at Birmingham
1665 University Blvd., Birmingham, AL 35294 (USA)
Tel. +1 205 934 4907, Fax +1 205 975 2541, E-Mail htiwari@uab.edu


 goto top of outline Article Information

Published online: March 31, 2008
Number of Print Pages : 20
Number of Figures : 1, Number of Tables : 2, Number of References : 192


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 66, No. 2, Year 2008 (Cover Date: March 2008)

Journal Editor: Devoto M. (Philadelphia, Pa.)
ISSN: 0001–5652 (Print), eISSN: 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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