THE AFFECTED SIB METHOD .3. SELECTION AND RECOMBINATION

  • 1 January 1984
    • journal article
    • research article
    • Vol. 36  (2) , 352-362
Abstract
The affected sib-pair method was used to investigate the mode of inheritance, and to estimate the disease allele frequency, for a number of HLA-associated diseases. One of the assumptions of the original sib-pair method is that the disease confers no selective disadvantage on affected individuals. This is obviously not the situation for most diseases. The expected HLA haplotype-sharing distribution was determined among affected sib-pairs when selection against individuals with the disease is taken into account. If the mode of inheritance of the selectively disadvantageous disease is recessive or additive, the original affected sib-pair analysis ignoring selection, still estimates the true mode of inheritance, but usually yields an underestimate of the disease allele frequency. For intermediate and dominant models of disease predisposition, both the estimates of the degree of penetrance of the disease genotypes and the disease allele frequency, are altered if selection is ignored in the analysis. Allowing for recombination between the disease locus and the HLA region does not affect the determination of the mode of inheritance of the disease if it is recessive or additive; in other cases the estimate of the mode of inheritance is affected. The disease allele frequency is overestimated when nonzero recombination is ignored for all the modes of inheritance that were studied.