- Family data
- Latent disease locus
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.
Copyright © 2009 S. Karger AG, Basel
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Antoniou AC, Easton DF: Polygenic inheritance of breast cancer: Implications for design of association studies. Genet Epidemiol 2003;25:190–202.
- Houlston RS, Peto J: The search for low-penetrance cancer susceptibility alleles. Oncogene 2004;23:6471–6476.
- 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.
- Whittemore AS: Estimating genetic association parameters from family data. Biometrika 2004;91:219–225.
- 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.
- International HapMap Consortium: A haplotype map of the human genome. Nature 2005;437:1299–1320.
- Stram DO: Tag snp selection for association studies. Genet Epidemiol 2004;27:365–374.
- Boehringer S: Estimation of association parameters in family based association studies. Ph.D. thesis, University Dortmund, Germany, Institute of Statistics, 2007.
- 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.
- 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.
- Laird NM, Horvath S, Xu X: Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000;19(suppl 1):S36–S42.
- 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.
- Jorm AF, Korten AE, Henderson AS: The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 1987;76:465–479.
- 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.
- Chen WM, Abecasis GR: Family-based association tests for genomewide association scans. Am J Hum Genet 2007;81:913–926.
- Hochberg Y, Benjamini Y: More powerful procedures for multiple significance testing. Stat Med 1990;9:811–818.
- Huang BE, Amos CI, Lin DY: Detecting haplotype effects in genomewide association studies. Genet Epidemiol 2007;31:803–812.
Institut für Humangenetik, Universitätsklinikum Essen
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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
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
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