Sodium transport comprises a set of interacting systems. Consequently, a defective sodium transport gene affects multiple sodium transport systems, and a sodium transport variable measured on a sample of individuals reflects genetic variation from a number of different genes, complicating the task of identifying the effect of a single gene. To test for genes which affect sodium transport, we first applied principal components analysis to 14 variables related to sodium transport, thereby defining uncorrelated sources of variation in the variables. The sample consisted of 1,218 members of 68 pedigrees ascertained through probands with early-onset stroke, hypertension, or coronary heart disease. Segregation analysis of the 14 principal components scores provided evidence for 8 genetic variants which alter sodium transport. One of the 8 variants is recessive, has homozygous genotype frequency estimated as 8.8% of the population, and increases sodium-lithium countertransport, the passive sodium leak, body mass index, and triglyceride; the genetic variant may coincide with an insulin resistance gene. A second of the 8 variants is also recessive, has homozygous genotype frequency estimated as 7.4% of the population, and increases intraerythrocytic sodium and the passive sodium leak while decreasing sodium pump number; the genetic variant may reduce pump number. Two of the 8 variants substantially increase sodium-lithium countertransport; frequency estimates for heterozygotes for the dominant variant and homozygotes for the recessive variant equal 1.8% and 3.1 %, respectively. Another of the 8 variants is recessive, has homozygous genotype frequency estimated as 1.9%, and increases body mass index. Each of the 3 remaining variants is rare and expressed in less than 1 % of the sample. @ 1994 Wiley-Liss, Inc.