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Vol. 67, No. 4, 2009
Issue release date: March 2009
Section title: Original Paper
Hum Hered 2009;67:226–236
(DOI:10.1159/000194976)

A Model for Fine Mapping in Family Based Association Studies

Boehringer S.a · Pfeiffer R.M.b
aInstitut für Humangenetik, Universitätsklinikum Essen, Essen, Germany; bBiostatistics Branch, National Cancer Institute, Bethesda, Md., USA
email Corresponding Author

Abstract

Genome wide association studies for complex diseases are typically followed by more focused characterization of the identified genetic region. We propose a latent class model to evaluate a candidate region with several measured markers using observations on families. The main goal is to estimate linkage disequilibrium (LD) between the observed markers and the putative true but unobserved disease locus in the region. Based on this model, we estimate the joint distribution of alleles at the observed markers and the unobserved true disease locus, and a penetrance parameter measuring the impact of the disease allele on disease risk. A family specific random effect allows for varying baseline disease prevalences for different families. We present a likelihood framework for our model and assess its properties in simulations. We apply the model to an Alzheimer data set and confirm previous findings in the ApoE region.

© 2009 S. Karger AG, Basel


  

Key Words

  • Family data
  • Likelihood
  • Haplotypes
  • Latent disease locus
  • Alzheimer

References

  1. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, San-Giovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J: Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–389.
  2. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, Green T, Kuballa P, Barmada MM, Datta LW, Shugart YY, Griffiths AM, Targan SR, Ippoliti AF, Bernard EJ, Mei L, Nicolae DL, Regueiro M, Schumm LP, Steinhart AH, Rotter JI, Duerr RH, Cho JH, Daly MJ, Brant SR: Genomewide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007;39:596–604.
  3. Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, Carlsson LMS, Kiess W, Vatin V, Lecoeur C, Delplanque J, Vaillant E, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, Stunff CL, Bougnères P, Kovacs P, Marre M, Balkau B, Cauchi S, Chèvre JC, Froguel P: Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007;39:724–726.
  4. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, Walters GB, Styrkarsdottir U, Gretarsdottir S, Emilsson V, Ghosh S, Baker A, Snorradottir S, Bjarnason H, Ng MCY, Hansen T, Bagger Y, Wilensky RL, Reilly MP, Adeyemo A, Chen Y, Zhou J, Gudnason V, Chen G, Huang H, Lashley K, Doumatey A, So WY, Ma RCY, Andersen G, Borch-Johnsen K, Jorgensen T, van Vliet-Ostaptchouk JV, Hofker MH, Wijmenga C, Christiansen C, Rader DJ, Rotimi C, Gurney M, Chan JCN, Pedersen O, Sigurdsson G, Gulcher JR, Thorsteinsdottir U, Kong A, Stefansson K: A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 2007;39:770–775.
  5. Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, Wacholder S, Minichiello MJ, Fearnhead P, Yu K, Chatterjee N, Wang Z, Welch R, Staats BJ, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cancel-Tassin G, Cussenot O, Valeri A, Andriole GL, Gelmann EP, Tucker M, Gerhard DS, Fraumeni JF, Hoover R, Hunter DJ, Chanock SJ, Thomas G: Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007;39:645–649.
  6. Teng J, Risch N: The relative power of family-based and case-control designs for linkage disequilibrium studies of complex human diseases. ii. individual genotyping. Genome Res 1999;9:234–241.
  7. Spielman RS, McGinnis RE, Ewens WJ: Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993;52:506–516.
  8. Rabinowitz D, Laird N: A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000;50:211–223.
  9. Antoniou AC, Easton DF: Polygenic inheritance of breast cancer: Implications for design of association studies. Genet Epidemiol 2003;25:190–202.
  10. Houlston RS, Peto J: The search for low-penetrance cancer susceptibility alleles. Oncogene 2004;23:6471–6476.
  11. Whittemore AS, Tu IP: Detection of disease genes by use of family data. I. Likelihood-based theory. Am J Hum Genet 2000;66:1328–1340.
  12. Whittemore AS: Estimating genetic association parameters from family data. Biometrika 2004;91:219–225.

    External Resources

  13. Wang T, Weir B, Zeng ZB: A population-based latent variable approach for association mapping of quantitative trait loci. Ann Hum Genet 2006;70:506–523.
  14. International HapMap Consortium: A haplotype map of the human genome. Nature 2005;437:1299–1320.
  15. Stram DO: Tag snp selection for association studies. Genet Epidemiol 2004;27:365–374.
  16. Boehringer S: Estimation of association parameters in family based association studies. Ph.D. thesis, University Dortmund, Germany, Institute of Statistics, 2007.
  17. Pfeiffer RM, Gail MH: Sample size calculations for population- and family-based case-control association studies on marker genotypes. Genet Epidemiol 2003;25:136–148.
  18. Horvath S, Xu X, Laird NM: The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 2001;9:301–306.
  19. Laird NM, Horvath S, Xu X: Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000;19(suppl 1):S36–S42.
  20. Martin ER, Lai EH, Gilbert JR, Rogala AR, Afshari AJ, Riley J, Finch KL, Stevens JF, Livak KJ, Slotterbeck BD, Slifer SH, Warren LL, Conneally PM, Schmechel DE, Purvis I, Pericak-Vance MA, Roses AD, Vance JM: SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease. Am J Hum Genet 2000;67:383–394.
  21. Jorm AF, Korten AE, Henderson AS: The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 1987;76:465–479.
  22. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE: Protective effect of apolipoprotein e type 2 allele for late onset Alzheimer disease. Nat Genet 1994;7:180–184.
  23. Chen WM, Abecasis GR: Family-based association tests for genomewide association scans. Am J Hum Genet 2007;81:913–926.
  24. Hochberg Y, Benjamini Y: More powerful procedures for multiple significance testing. Stat Med 1990;9:811–818.
  25. Huang BE, Amos CI, Lin DY: Detecting haplotype effects in genomewide association studies. Genet Epidemiol 2007;31:803–812.

  

Author Contacts

Stefan Boehringer
Institut für Humangenetik, Universitätsklinikum Essen
Hufelandstr. 55, DE–45122 Essen (Germany)
Tel. +49 201 723 4533, Fax +49 201 735 5900
E-Mail correspondence@s-boehringer.org

  

Article Information

Received: March 3, 2008
Accepted after revision: August 4, 2008
Published online: January 27, 2009
Number of Print Pages : 11
Number of Figures : 0, Number of Tables : 6, Number of References : 25

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 67, No. 4, Year 2009 (Cover Date: March 2009)

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

Genome wide association studies for complex diseases are typically followed by more focused characterization of the identified genetic region. We propose a latent class model to evaluate a candidate region with several measured markers using observations on families. The main goal is to estimate linkage disequilibrium (LD) between the observed markers and the putative true but unobserved disease locus in the region. Based on this model, we estimate the joint distribution of alleles at the observed markers and the unobserved true disease locus, and a penetrance parameter measuring the impact of the disease allele on disease risk. A family specific random effect allows for varying baseline disease prevalences for different families. We present a likelihood framework for our model and assess its properties in simulations. We apply the model to an Alzheimer data set and confirm previous findings in the ApoE region.

© 2009 S. Karger AG, Basel


  

Author Contacts

Stefan Boehringer
Institut für Humangenetik, Universitätsklinikum Essen
Hufelandstr. 55, DE–45122 Essen (Germany)
Tel. +49 201 723 4533, Fax +49 201 735 5900
E-Mail correspondence@s-boehringer.org

  

Article Information

Received: March 3, 2008
Accepted after revision: August 4, 2008
Published online: January 27, 2009
Number of Print Pages : 11
Number of Figures : 0, Number of Tables : 6, Number of References : 25

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 67, No. 4, Year 2009 (Cover Date: March 2009)

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

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


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 3/6/2008
Accepted: 4/8/2008
Published online: 1/27/2009
Issue release date: March 2009

Number of Print Pages: 11
Number of Figures: 0
Number of Tables: 6

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.

References

  1. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, San-Giovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J: Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–389.
  2. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, Green T, Kuballa P, Barmada MM, Datta LW, Shugart YY, Griffiths AM, Targan SR, Ippoliti AF, Bernard EJ, Mei L, Nicolae DL, Regueiro M, Schumm LP, Steinhart AH, Rotter JI, Duerr RH, Cho JH, Daly MJ, Brant SR: Genomewide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007;39:596–604.
  3. Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, Carlsson LMS, Kiess W, Vatin V, Lecoeur C, Delplanque J, Vaillant E, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, Stunff CL, Bougnères P, Kovacs P, Marre M, Balkau B, Cauchi S, Chèvre JC, Froguel P: Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007;39:724–726.
  4. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, Walters GB, Styrkarsdottir U, Gretarsdottir S, Emilsson V, Ghosh S, Baker A, Snorradottir S, Bjarnason H, Ng MCY, Hansen T, Bagger Y, Wilensky RL, Reilly MP, Adeyemo A, Chen Y, Zhou J, Gudnason V, Chen G, Huang H, Lashley K, Doumatey A, So WY, Ma RCY, Andersen G, Borch-Johnsen K, Jorgensen T, van Vliet-Ostaptchouk JV, Hofker MH, Wijmenga C, Christiansen C, Rader DJ, Rotimi C, Gurney M, Chan JCN, Pedersen O, Sigurdsson G, Gulcher JR, Thorsteinsdottir U, Kong A, Stefansson K: A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 2007;39:770–775.
  5. Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, Wacholder S, Minichiello MJ, Fearnhead P, Yu K, Chatterjee N, Wang Z, Welch R, Staats BJ, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cancel-Tassin G, Cussenot O, Valeri A, Andriole GL, Gelmann EP, Tucker M, Gerhard DS, Fraumeni JF, Hoover R, Hunter DJ, Chanock SJ, Thomas G: Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007;39:645–649.
  6. Teng J, Risch N: The relative power of family-based and case-control designs for linkage disequilibrium studies of complex human diseases. ii. individual genotyping. Genome Res 1999;9:234–241.
  7. Spielman RS, McGinnis RE, Ewens WJ: Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993;52:506–516.
  8. Rabinowitz D, Laird N: A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000;50:211–223.
  9. Antoniou AC, Easton DF: Polygenic inheritance of breast cancer: Implications for design of association studies. Genet Epidemiol 2003;25:190–202.
  10. Houlston RS, Peto J: The search for low-penetrance cancer susceptibility alleles. Oncogene 2004;23:6471–6476.
  11. Whittemore AS, Tu IP: Detection of disease genes by use of family data. I. Likelihood-based theory. Am J Hum Genet 2000;66:1328–1340.
  12. Whittemore AS: Estimating genetic association parameters from family data. Biometrika 2004;91:219–225.

    External Resources

  13. Wang T, Weir B, Zeng ZB: A population-based latent variable approach for association mapping of quantitative trait loci. Ann Hum Genet 2006;70:506–523.
  14. International HapMap Consortium: A haplotype map of the human genome. Nature 2005;437:1299–1320.
  15. Stram DO: Tag snp selection for association studies. Genet Epidemiol 2004;27:365–374.
  16. Boehringer S: Estimation of association parameters in family based association studies. Ph.D. thesis, University Dortmund, Germany, Institute of Statistics, 2007.
  17. Pfeiffer RM, Gail MH: Sample size calculations for population- and family-based case-control association studies on marker genotypes. Genet Epidemiol 2003;25:136–148.
  18. Horvath S, Xu X, Laird NM: The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 2001;9:301–306.
  19. Laird NM, Horvath S, Xu X: Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000;19(suppl 1):S36–S42.
  20. Martin ER, Lai EH, Gilbert JR, Rogala AR, Afshari AJ, Riley J, Finch KL, Stevens JF, Livak KJ, Slotterbeck BD, Slifer SH, Warren LL, Conneally PM, Schmechel DE, Purvis I, Pericak-Vance MA, Roses AD, Vance JM: SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease. Am J Hum Genet 2000;67:383–394.
  21. Jorm AF, Korten AE, Henderson AS: The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 1987;76:465–479.
  22. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE: Protective effect of apolipoprotein e type 2 allele for late onset Alzheimer disease. Nat Genet 1994;7:180–184.
  23. Chen WM, Abecasis GR: Family-based association tests for genomewide association scans. Am J Hum Genet 2007;81:913–926.
  24. Hochberg Y, Benjamini Y: More powerful procedures for multiple significance testing. Stat Med 1990;9:811–818.
  25. Huang BE, Amos CI, Lin DY: Detecting haplotype effects in genomewide association studies. Genet Epidemiol 2007;31:803–812.