Major gene effect on body mass index: The role of energy intake and energyexpenditure

The evidence for a major gene for body mass index (BMI) was investigated us ing complex segregation analysis (POINTER) in 1691 individuals belonging to 432 nuclear families residing in the Chittoor district of Andhra Pradesh, India. Since the BMI is significantly correlated with energy intake (EI) an d energy expenditure of activity (EEA), the effects of each were removed fr om the BMI using regression analysis, and the segregation analysis was repe ated on the energy-adjusted BMI. For BMI, a putative major locus could not be ruled out, and the effect (q = 0.25, accounting for 37% of the phenotypi c variance) was remarkably similar to that reported in Western populations. After adjusting the BMI for EI and EEA, however, no evidence in support of a major gene could be observed, suggesting either that EI and EEA mediate the expression of the major gene effect on BMI, or that the same major gene may influence both traits. The pleiotropy hypothesis was further explored using a simple bivariate familial correlation model, in which the significa nce of familial cross-trait correlations (e.g., BMI in parents with BMI as predicted from the energy variables in the offspring) was examined. The cro ss-trait resemblance between the two measures was significant for all biolo gical relatives, verifying the presence of shared heritable determinants (i .e., the same gene[s] and/or familial environments) accounting for 58% of t he covariation. The significant cross-trait spouse correlations further sug gested that at least part of the cross-trait resemblance may be due to shar ed environmental factors. Therefore, we conclude that there is strong evide nce for shared genetic effects between BMI and the energy variables.