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

Abstract

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 relatively isolated population, in which the incidence and prevalence of Type 2 diabetes, gallbladder disease, and rheumatoid arthritis (RA) are significantly increased compared with the general U.S. population. A previous study of RA in the Pima utilizing traditional methods failed to detect a genetic effect on the occurrence of the disease. Methods: Our approach involved constructing a genealogy for this population and using a genealogic index to investigate familial aggregation. We developed an algorithm to identify biological relationships among 88 RA cases versus 4,000 subsamples of age-matched individuals from the same population. Kinship coefficients were calculated for all possible pairs of RA cases, and similarly for the subsamples. Results: 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 of second cousin, supporting a genetic effect in the familial aggregation. The mean inbreeding coefficient for the Pima was 0.00009, similar to that reported 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 population as the "unit" in which to assess familial aggregation may be advantageous, especially if there are a limited number of cases in the study population.