Single Marker Family-Based Association Analysis Conditional on Parental Information

  • Ren-Hua Chung
  • Daniel D. Kinnamon
  • Eden R. Martin
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1666)

Abstract

Family-based designs have been commonly used in association studies. Different family structures such as extended pedigrees and nuclear families, including parent–offspring triads and families with multiple affected siblings (multiplex families), can be ascertained for family-based association analysis. Flexible association tests that can accommodate different family structures have been proposed. The pedigree disequilibrium test (PDT) (Martin et al., Am J Hum Genet 67:146–154, 2000) can use full genotype information from general (possibly extended) pedigrees with one or multiple affected siblings but requires parental genotypes or genotypes of unaffected siblings. On the other hand, the association in the presence of linkage (APL) test (Martin et al., Am J Hum Genet 73:1016–1026, 2003) is restricted to nuclear families with one or more affected siblings but can infer missing parental genotypes properly by accounting for identity-by-descent (IBD) parameters. Both the PDT and APL test are powerful association tests in the presence of linkage and can be used as complementary tools for association analysis. This chapter introduces these two tests and compares their properties. Recommendations and notes for performing the tests in practice are provided.

Key words

Family-based association test Linkage disequilibrium Transmission statistics Nontransmission statistics Parental information EM algorithm Rare variants Genome-wide association Extended pedigree Nuclear family Parallelization Population stratification 

References

  1. 1.
    Ma DQ, Salyakina D, Jaworski JM et al (2009) A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann Hum Genet 73:263–273CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    International Multiple Sclerosis Genetics Consortium, Hafler DA, Compston A et al (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357:851–862CrossRefGoogle Scholar
  3. 3.
    Sklar P, Gabriel SB, McInnis MG et al (2002) Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry 7:579–593CrossRefPubMedGoogle Scholar
  4. 4.
    Oudot T, Lesueur F, Guedj M et al (2009) An association study of 22 candidate genes in psoriasis families reveals shared genetic factors with other autoimmune and skin disorders. J Invest Dermatol 129:2637–2645CrossRefPubMedGoogle Scholar
  5. 5.
    Lander ES, Schork NJ (1994) Genetic dissection of complex traits. Science 265:2037–2048CrossRefPubMedGoogle Scholar
  6. 6.
    Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506–516PubMedPubMedCentralGoogle Scholar
  7. 7.
    Martin ER, Kaplan NL, Weir BS (1997) Tests for linkage and association in nuclear families. Am J Hum Genet 61:439–448CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Martin ER, Monks SA, Warren LL, Kaplan NL (2000) A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 67:146–154CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Spielman RS, Ewens WJ (1998) A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am J Hum Genet 62:450–458CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Boehnke M, Langefeld CD (1998) Genetic association mapping based on discordant sib pairs: the discordant-alleles test. Am J Hum Genet 62:950–961CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Horvath S, Laird NM (1998) A discordant-sibship test for disequilibrium and linkage: no need for parental data. Am J Hum Genet 63(6):1886–1897CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Martin ER, Bass MP, Hauser ER, Kaplan NL (2003) Accounting for linkage in family-based tests of association with missing parental genotypes. Am J Hum Genet 73:1016–1026CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Clayton D (1999) A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 65:1170–1177CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Dudbridge F (2008) Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 66:87–98CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Knapp M (1999) The transmission/disequilibrium test and parental-genotype reconstruction: The reconstruction-combined transmission/disequilibrium test. Am J Hum Genet 64:861–870CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Rabinowitz D, Laird N (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 50:211–223CrossRefPubMedGoogle Scholar
  17. 17.
    Chung RH, Hauser ER, Martin ER (2006) The APL test: extension to general nuclear families and haplotypes and examination of its robustness. Hum Hered 61:189–199CrossRefPubMedGoogle Scholar
  18. 18.
    Martin ER, Bass MP, Kaplan NL (2001) Correcting for a potential bias in the pedigree disequilibrium test. Am J Hum Genet 68:1065–1067CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Martin ER, Bass MP, Gilbert JR, Pericak-Vance MA, Hauser ER (2003) Genotype-based association test for general pedigrees: the genotype-PDT. Genet Epidemiol 25:203–213CrossRefPubMedGoogle Scholar
  20. 20.
    Chung RH, Morris RW, Zhang L, Li YJ, Martin ER (2007) X-APL: an improved family-based test of association in the presence of linkage for the X chromosome. Am J Hum Genet 80:59–68CrossRefPubMedGoogle Scholar
  21. 21.
    Gregory SG, Schmidt S, Seth P et al (2007) Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 39:1083–1091CrossRefPubMedGoogle Scholar
  22. 22.
    Martin ER, Scott WK, Nance MA et al (2001) Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease. JAMA 286:2245–2250CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Schmidt S, Hauser MA, Scott WK et al (2006) Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet 78:852–864CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wang L, Hauser ER, Shah SH et al (2007) Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease. Am J Hum Genet 80:650–663CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Prokunina L, Castillejo-Lopez C, Oberg F et al (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32:666–669CrossRefPubMedGoogle Scholar
  26. 26.
    Deak KL, Dickerson ME, Linney E et al (2005) Analysis of ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2 in human neural tube defects suggests a possible association with alleles in ALDH1A2. Birth Defects Res A Clin Mol Teratol 73:868–875CrossRefPubMedGoogle Scholar
  27. 27.
    Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Efron B, Tibshirani RJ (1993) An introduction to the bootstrap. Chapman & Hall, New YorkCrossRefGoogle Scholar
  29. 29.
    Chung RH, Schmidt S, Martin ER, Hauser ER (2008) Ordered-subset analysis (OSA) for family-based association mapping of complex traits. Genet Epidemiol 32:627–637CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hauser ER, Watanabe RM, Duren WL, Bass MP, Langefeld CD, Boehnke M (2004) Ordered subset analysis in genetic linkage mapping of complex traits. Genet Epidemiol 27:53–63CrossRefPubMedGoogle Scholar
  31. 31.
    Zhang S, Zhang K, Li J, Sun F, Zhao H (2001) Test of association for quantitative traits in general pedigrees: the quantitative pedigree disequilibrium test. Genet Epidemiol 21(Suppl 1):S370–S375CrossRefPubMedGoogle Scholar
  32. 32.
    Abecasis GR, Cardon LR, Cookson WOC (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292CrossRefPubMedGoogle Scholar
  33. 33.
    Rabinowitz D, Laird NM (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 504:227–233Google Scholar
  34. 34.
    Liang K, Zeger SL (1986) Longitudinal data analysis using generalized linear models. Biometrika 73:13–22CrossRefGoogle Scholar
  35. 35.
    Stroup WW (2012) Generalized linear mixed models: modern concepts, methods and applications. CRC Press, Boca Raton, FLGoogle Scholar
  36. 36.
    Chung RH, Schmidt MA, Morris RW, Martin ER (2010) CAPL: a novel association test using case-control and family data and accounting for population stratification. Genet Epidemiol 7:747–755CrossRefGoogle Scholar
  37. 37.
    Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155:945–959PubMedPubMedCentralGoogle Scholar
  38. 38.
    Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909CrossRefPubMedGoogle Scholar
  39. 39.
    Li B, Leal SM (2008) Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet 83:311–321CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Madsen BE, Browning SR (2009) A groupwise association test for rare mutations using a weighted sum statistic. PLoS Genet 5:e1000384CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Morris AP, Zeggini E (2010) An evaluation of statistical approaches to rare variant analysis in genetic association studies. Genet Epidemiol 34:188–193CrossRefPubMedGoogle Scholar
  42. 42.
    Price AL, Kryukov GV, de Bakker PI, Purcell SM, Staples J, Wei LJ, Sunyaev SR (2010) Pooled association tests for rare variants in exon-resequencing studies. Am J Hum Genet 86:832–838CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kinnamon DD, Hershberger RE, Martin ER (2012) Reconsidering association testing methods using single-variant test statistics as alternatives to pooling tests for sequence data with rare variants. PLoS One 7(2):e30238CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2017

Authors and Affiliations

  • Ren-Hua Chung
    • 1
  • Daniel D. Kinnamon
    • 2
  • Eden R. Martin
    • 3
  1. 1.Division of Biostatistics and BioinformaticsInstitute of Population Health Sciences, National Health Research InstitutesNewyorkTaiwan
  2. 2.Division of Human Genetics, Department of Internal MedicineThe Ohio State University Wexner Medical CenterColumbusUSA
  3. 3.John P. Hussman Institute for Human Genomics, Leonard M. Miller School of MedicineUniversity of MiamiMiamiUSA

Personalised recommendations