Regional fat distribution is related to higher risks of cardiovascular morbidity and mortality, independent of general obesity. In particular, a centralized pattern of fat deposition, characterized by greater abdominal stores relative to extremity stores, is associated with a higher propensity to metabolic complications. Motivated by these considerations, we have initiated a systematic investigation of several measures of regional fat distribution aimed at the identification of possible major gene effects. Two measures approximate the size of subcutaneous fat stores: the sum of six skinfold thicknesses (SF6 = abdominal + suprailiac + subscapular + calf + triceps + biceps), and the sum of three trunk skinfold thicknesses (TSF3 = abdominal + suprailiac + subscapular). Both of these phenotypes are highly correlated with total fat mass, 0.83 and 0.78 for SF6 and TSF3, respectively. The trunk to extremity ratio [TER = TSF3/ (calf + triceps + biceps)] is perhaps the most important of these phenotypes insofar as it is an index of centralized obesity; it is modestly correlated with fat mass (r = 0.18). Each of these phenotypes was adjusted for total fat mass by regression prior to analysis so that we could examine genetic effects on these measures of regional fat distribution without the confounding influence of the determinants of fat mass itself. Segregation analysis of SF6 and TSF3 controlled for total fat mass suggests the presence of a major effect underlying the observed phenotypic distribution; however, tests on the transmission probabilities did not substantiate the segregation of a Mendelian gene.(ABSTRACT TRUNCATED AT 250 WORDS)