Genealogy construction in a historically isolated population: Application to genetic studies of rheumatoid arthritis in the Pima Indian

Purpose: Due to the characteristics of complex traits, many traits may not be amenable to traditional epidemiologic methods. We illustrate an approach that defines an isolated population as the "unit" for carrying out studies of complex disease. We provide an example using the Pima Indians, a relati vely isolated population, in which the incidence and prevalence of Type 2 d iabetes, gallbladder disease, and rheumatoid arthritis (RA) are significant ly increased compared with the general U.S. population. A previous study of RA in the Pima utilizing traditional methods failed to detect a genetic ef fect on the occurrence of the disease. Methods: Our approach involved const ructing a genealogy for this population and using a genealogic index to inv estigate familial aggregation. We developed an algorithm to identify biolog ical relationships among 88 RA cases Versus 4,000 subsamples of age-matched individuals from the same population. Kinship coefficients were calculated for ail possible pairs of RA cases, and similarly for the subsamples. Resu lts: The sum of the kinship coefficient among all combination of RA pairs, 5.92, was significantly higher than the average of the 4,000 subsamples, 1. 99 (p < 0.001), and was elevated over that of the subsamples to the level o f second cousin, supporting a genetic effect in the familial aggregation. T he mean inbreeding coefficient for the Pima was 0.00009, similar to that re ported for other populations; none of the RA cases were inbred. Conclusions : The Pima genealogy can be anticipated to provide valuable information for the genetic study of diseases other than RA. Defining an isolated populati on as the "unit" in which to assess familial aggregation may be advantageou s, especially if there are a limited number of cases in the study populatio n.