Methods based on relative pairs

The underlying principle of the affected sib-pair approach is simple. For any given locus the probabilities that siblings share 0, 1, or 2 alleles that are identical by descent from their parents is respectively %, %, %. On the other hand, if both members of a sib pair are affected by the same disease and we are studying a locus close to a gene that confers susceptibility to that disease, there will be increased allele sharing. This will occur irrespective of the mode of transmission of the susceptibility gene and hence simple non-parametric statistics can be used to test whether there is any perturbation of the expected identical-by-descent proportions. Affected sib-pair methods are therefore robust and are now generally considered to be the method of choice in detecting linkage in oligogenic or polygenic disorders. In order to be certain that a pair of siblings share alleles identical by descent, one needs to know their parents' genotypes. Otherwise it could be that a shared allele identical by state results from one of the pair having inherited it from the father and the other from the mother. However, an advantage of using highly polymorphic single sequence repeat polymorphisms is that it may not always be necessary to genotype parents, i.e. where the population is reasonably homogenous and where gene frequencies can be estimated, it is possible to compute the likelihood that a pair who share one or two alleles identical by state are truly identical by descent. This means that in return for a fairly modest reduction in power (because one is now dealing with a probability rather than a certainty of counting alleles that are identical by descent) there is a halving in the amount of genotyping that needs to be done. (20) In our own experience, the other advantage of being able to make do without parental genotypes is that they are often difficult to obtain in adult-onset disorders such as schizophrenia.

Another use of sib-pair methods is in studying continuous traits (e.g. height, weight, personality test scores) to attempt to detect the quantitative trait loci that contribute to their heritability.(21 One approach is to select probands who have extreme scores on some quantitative measure and investigate the extent to which marker allele sharing by siblings predicts the regression to the population mean of the siblings' scores. (22) This has been successfully used in mapping a quantitative trait locus contributing to reading ability in children. Unfortunately the drawback of such methods and of sib-pair linkage approaches generally is that they are only capable of detecting moderately large effects. This means that a quantitative trait locus contributing less than about 10 per cent of the variance or a disease susceptibility locus conferring a relative risk of less than 2 will probably require very large samples running into several hundreds, perhaps thousands, of pairs. If we assume that most common diseases and complex behaviours involve the combined action of many genes of small effect, complementary strategies based on allelic association are required.

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