We examined the mode of inheritance of rheumatoid arthritis (RA) and estimated the genetic contribution of the HLA-linked locus to the development of RA using data from 111 multiplex families (54 London, 57 Cleveland), and 43 randomly ascertained patients (Seattle). HLA-DR4 was present in 78 multiplex probands (70%); a further 16 probands who were negative for DR4 were positive for DR1. Both DR4 and DR1 were significantly in excess when compared to control population frequencies (P less than 0.001); an additional finding was an excess of DR7, although the numbers of probands with DR7 were small. Despite the well-established HLA association with RA, neither recessive nor additive (dominant) modes of inheritance, nor any intermediate models have been ruled out using affected sib-pair and antigen genotype frequency among patients (AGFAP) methods. However, in our study the AGFAP data for HLA-DR4 and DR1 were close to recessive expectations (P = ns) while an additive (dominant) mode of inheritance was rejected (P less than 0.001). The same results were obtained by an independent method which considered HLA-DR transmission from affected parents to their affected children. The affected sib-pair haplotype sharing method showed deviation from random expectations but did not allow discrimination between recessive and additive (dominant) modes. The effect of the HLA-linked locus on familiarity accounted for only a 1.61-fold increased risk to sibs over the population prevalence, compared to an observed value of 3.90. This indicated that there could be at least one other non-HLA locus predisposing to RA with a weight that is slightly greater than that of HLA.

Rheumatoid arthritis (RA) is a disease of unknown etiology but with a presumed complex pattern of inheritance. Risch [Am J Hum Genet 46:222-228, 1990] has shown that the recurrence risk ratio, lambda R, (which is defined as the risk to type R relatives vs. the population prevalence) can be used to evaluate patterns of inheritance in genetically complex diseases. We have used the Risch theory to examine some multiple locus models of inheritance in RA. Recurrence risk ratios in MZ twins and in 1st, 2nd, and 3rd degree relatives are summarized from the literature. The limited data available supports at least a two-locus model of inheritance for RA (assuming that one locus is HLA). Better estimates of the recurrence risk ratios in RA families are required so that the Risch theory can be pursued further.

It is shown that in a hierarchical island model, in which demes within a neighborhood exchange migrants at a much higher rate than do demes in different neighborhoods, hierarchical F statistics introduced by S. Wright can indicate the extent of gene flow within and between neighborhoods. At equilibrium, the within-neighborhood inbreeding coefficient, FSN, is approximately 1/(1 + 4Nm1) where N is the deme size and m1 is the migration rate among demes in the same neighborhood. The between-neighborhood inbreeding coefficient, FNT, is approximately 1/(1 + 4Ndm2) where d is the number of demes in a neighborhood and m2 is the migration rate among demes in different neighborhoods.