Family‐based Association Test (FBAT)

Abstract

Statistical tests of association are commonly used to confirm or exclude a relationship between disease and selected genes. Tests which are based on data from unrelated individuals are very popular, but can be biased if the sample contains individuals with different genetic ancestries. Family‐based Association tests avoid the problem of bias due to mixed ancestry by using within family comparisons. Many different family designs are possible, the most popular using parents and offspring, but others use just sibships. Dichotomous, measured and time‐to‐onset phenotypes can be accommodated. FBATs are generally less powerful than tests based on a sample of unrelated individuals, but special settings exist, for example testing for rare variants with affected offspring and their parents, where the family design has a power advantage.

Key Concepts:

  • Genetic tests based on population samples can be biased due to differing genetic ancestries.

  • Association designs using family members can avoid bias by using within family comparison.

  • The simplest family test is the TDT which uses affected offspring and their parents.

  • FBAT refers to a class of tests for family designs that can accommodate any type of genetic model, any phenotype and any family configuration, e.g. parents and their offspring, sibships or even general pedigrees.

  • In general, FBAT's are less powerful than their population‐based counter‐parts, and they generally also require more genotyping, but in some circumstances, e.g. for rare variants and in testing for gene–environment interactions, they can be more powerful.

Keywords: genetic association test; TDT; family design; trios; discordant sibship test; missing parents; Mendel's laws; linkage; linkage disequilibrium

Figure 1.

Transmissions of genetic variants from parents to offspring is governed by Mendel's First Law of Segregation. It forms the basis of the TDT.

Figure 2.

Using the Sufficient Statistic to calculate the distribution of offspring genotypes under different nuclear family configurations.

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References

Abecasis GR, Cardon LR and Cookson WO (2000) A general test of association for quantitative traits in nuclear families. American Journal of Human Genetics 66: 279–292.

Allison DB (1997) Transmission‐disequilibrium tests for quantitative traits. American Journal of Human Genetics 60: 676–690.

Cupples AL (2008) Family study designs in the age of genome‐wide association studies: experience from the Framingham Heart Study. Current Opinion in Lipidology 19: 144–150.

Dudbridge F (2008) Likelihood‐based association analysis for nuclear families and unrelated subjects with missing genotype data. Human Hereditary 66: 87–98.

Gauderman WJ (2003) Candidate gene association analysis for a quantitative trait. Genetic Epidemiology 25: 327–338.

Gordon D and Ott J (2001) Assessment and management of single nucleotide polymorphism genotype errors in genetic association analysis. Proceedings Symposium Biocomputing 18: 29.

Hoffmann TJ, Lange C, Vansteelandt S and Laird NM (2009) Gene‐environment interaction tests for dichotomous traits in trios and sibships. Genetic Epidemiology 33: 691–699.

Horvath S, Xu X and Laird NM (2001) The family based association test method: strategies for studying general genotype‐phenotype associations. European Journal of Human Genetics 9: 301–306.

Knapp M (1999) The transmission/disequilibrium tests and parental‐genotype reconstruction: the reconstruction‐combined transmission/disequilibrium test. American Journal of Human Genetics 64: 86170.

Laird NM, Horvath S and Xu X (2000) Implementing a unified approach to family based tests of association. Genetic Epidemiology 19: S36–S45.

Laird NM and Lange C (2006) Family based designs in the age of large‐scale gene‐association studies. Nature Reviews. Genetics 7: 385–394.

Lake SL, Blacker D and Laird NM (2000) Family based tests of association in the presence of linkage. American Journal of Human Genetics 67: 1515–1525.

Lange C, Blacker D and Laird NM (2004) Family based association tests for survival and time‐to‐onset analysis. Statistics in Medicine 23: 179–189.

Lange C and Laird NM (2002) Analytical sample size and power calculations for a general class of family based association tests: Dichotomous traits. American Journal of Human Genetics 71: 575–584.

Lunetta KL, Faraone SV, Biederman J and Laird NM (2000) Family based tests of association and linkage that use unaffected sibs, covariates, and interactions. American Journal of Human Genetics 66: 605–614.

Rabinowitz D and Laird NM (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker Information. Human Heredity 50: 211–223.

Schaid DJ and Sommer SS (1996) General score tests for association of genetic markers with disease using cases and their parents. Genetic Epidemiology 13: 423–449.

Spielman RS and Ewens RS (1998) A sibship test for linkage in the presence of association. American Journal of Human Genetics 62: 450–458.

Spielman RS, McGinnis RE and Ewens WJ (1993) Transmisson test for linkage disequilibrium: the insulin gene region and insulin‐dependent diabetes mellitus. American Journal of Human Genetics 53: 506–516.

Vansteelandt S, Demeo DL, Lasky‐Su J et al. (2008) Testing and estimating gene‐environment interactions in family based association studies. Biometrics 64: 458–467.

Witte JS, Gauderman WJ and Thomas DC (1999) Asymptotic bias and efficiency in case‐control studies of candidate genes and gene‐environment interactions: basic family designs. American Journal of Epidemiology 149: 693–705.

Further Reading

Ewens WJ, Li M and Spielman RS (2008) A review of family based tests for linkage disequilibrium between a quantitative trait and a genetic marker. PLoS Genetics 4: e1000180.

McGinnis R, Shiftman S and Darvasi A (2002) Power and efficiency of the TDT and case‐control design for association scans. Behavioral Genetics 32: 135–144.

Risch N and Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273: 1516–1517.

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How to Cite close
Laird, Nan M(Jan 2011) Family‐based Association Test (FBAT). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022500]