Core Laboratory utilization only. The Old Order Amish of Lancaster County, Pennsylvania migrated from Berne Switzerland in the mid-1700s. Initially numbering in the hundreds, they are now a population of over 2000. They represent a well-defined, genetically homogenous, caucasian population with very large sibships, a high degree of consanguinity, and well-documented genealogies. We are recruiting and phenotypically characterizing large multiplex pedigrees with noninsulin dependent diabetes mellitus (NIDDM) for a genome-wide search for susceptibility genes for this heterogeneous and polygenic disorder. To date, 900 subjects of a planned 1000 subjects have been studied. These individuals are from 76 two-and three-generation families constituting one extended pedigree and 2000 sib pairs. Of the first consecutive 258 subjects recruited, 16.2% had diabetes if they had a first degree relative with diabetes, compared to only 6.5% if there was no first degree relative with diabetes (RR 2.5; p=0.007; 95% CI 1.2-5.0). Phenotypic characterization includes family and medical history, anthropometry (height, weight, waist, hip, fat mass), 75 gram oral glucose tolerance test, hemoglobin A1c, and lipids. Automated genotyping using polymorphic short sequence tandem repeats (microsatellites) toward obtaining a 10 centimorgan map is proceeding at a rapid pace. Several different types of parametric and nonparametric analyses including affected sib pairs and pedigree member pair analysis, analysis of quantitative traits, and cosegregation analysis are in progress.