With possibly incomplete nuclear families, the family based association test (FBAT) method allows one to evaluate any test statistic that can be expressed as the sum of products (covariance) between an arbitrary function of an offspring's genotype with an arbitrary function of the offspring's phenotype. We derive expressions needed to calculate the mean and variance of these test statistics under the null hypothesis of no linkage. To give some guidance on using the FBAT method, we present three simple data analysis strategies for different phenotypes: dichotomous (affection status), quantitative and censored (eg, the age of onset). We illustrate the approach by applying it to candidate gene data of the NIMH Alzheimer Disease Initiative. We show that the RC-TDT is equivalent to a special case of the FBAT method. This result allows us to generalise the RC-TDT to dominant, recessive and multi-allelic marker codings. Simulations compare the resulting FBAT tests to the RC-TDT and the S-TDT. The FBAT software is freely available. European Journal of Human Genetics (2001) 9, 301 ± 306.

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We provide a general purpose family-based testing strategy for associating disease phenotypes with haplotypes when phase may be ambiguous and parental genotype data may be missing. These tests for linkage and association can be used in candidate gene studies with tightly linked markers. Our proposed weighted conditional approach extends the method described in Rabinowitz and Laird to multiple markers. It is attractive because it provides haplotype tests for family-based studies that are efficient and robust to population admixture, phenotype distribution specification, and ascertainment based on phenotypes. It can handle missing parental genotypes and/or missing phase in both offspring and parents. It yields either haplotype-specific (univariate) tests or multi-haplotype (global) tests. This extension has been implemented in the freely available software haplotype FBAT. We used the haplotype FBAT program to test for associations between asthma phenotypes and single nucleotide polymorphisms (SNPs) in the beta-2 adrenergic receptor gene. Whereas no single SNP showed significant association with asthma diagnosis or bronchodilator responsiveness (quantitative trait), a haplotype-based global test found a highly significant association with asthma diagnosis (P value <0.00005) and the measure of bronchodilator responsiveness (P value =0.016).

Microsatellites, comprising tandemly repeated short nucleotide sequences, are ubiquitous in eukaryotic genomes. Mutations within microsatellites are frequent, altering their overall length by insertion or deletion of a small number of repeat units, with a rate as high as 10(-3) in humans. Despite their high mutability, stable allele frequency distributions are typically observed for microsatellites in humans as well as other primates, although the mechanism maintaining these stable distributions remains unclear. Previous studies have suggested that microsatellite mutations occur more frequently in longer alleles and favour expansion. Generalizing these results has been hindered because the sample sizes were small, only a small subset of alleles for any marker was studied and the direction of mutation (expansion or contraction) was not rigorously determined. Here we examine 236 mutations at 122 tetranucleotide repeat markers and find that the rate of contraction mutations increases exponentially with allele size, whereas the rate of expansion mutations is constant across the entire allele distribution. The overall rate of expansion mutations does not differ from that of contractions. Our findings offer an explanation for the stationary allele distribution of microsatellites.