EVIDENCE FOR AT LEAST 2 MAJOR LOCI INFLUENCING HUMAN FATNESS

The genetics of human fatness has been the subject of many recent stud ies, motivated by the increased morbidity and mortality associated wit h obesity, as well as the increasing prevalence of overweight and obes ity. The body-mass index (BMI) and fat mass (FM), measured by underwat er weighing, were assessed for 1,630 individuals from similar to 300 f amilies from phase 1 of the Quebec Family Study. The two phenotypes ar e highly correlated (similar to.8) in adults, and previous segregation analysis revealed evidence for a recessive major gene for each trait. In our study we utilized bivariate segregation analysis to determine the source(s) of phenotypic correlation-namely, a pleiotropic major ge ne, shared familial factors/polygenes, or shared nontransmitted enviro nmental factors. Analysis was performed by use of the Pedigree Analysi s Package, with extensions to the bivariate case. Tests of hypotheses provided evidence for two pleiotropic recessive loci, together account ing for 64% and 47% of the variance in BMI and FM, respectively. Under the model, all sources of phenotypic correlation were significant: 73 % of the covariance was attributed to the pleiotropic major loci, 8% t o residual familial effects, and 19% to nontransmitted environmental f actors. The high degree of genetic identity between the two traits is not surprising, since the BMI often is used as a surrogate for FM; how ever, simultaneous analysis of both phenotypes enabled the detection o f a second major locus, which apparently does not affect extreme overw eight (as does the primary major locus) but which affects variation in the ''normal'' range.