Segregation analysis of body mass index in a large sample selected for obesity: The Swedish Obese Subjects Study

Objective: To investigate a major gene hypothesis for body mass index (BMI) in a large sample of probands (n = 2580, ages 37-57 years) who were select ed for obesity (BMI greater than or equal to 34 kg/m(2) for males and great er than or equal to 38 kg/m(2) for females), along with their spouses and f irst-degree relatives (n=11,204 family members). The probands were recruite d as part of an intervention trial assessing whether mortality and morbidit y were improved after surgical intervention for obesity as part of the Swed ish Obese Subjects (SOS) study. Methods and Procedures: The current analyses were based on BMI measures obt ained before intervention. Segregation analysis was carried out using the m ixed model implementation in PAP (Pedigree Analysis Package), which allowed for ascertainment correction and for genotype-dependent effects of covaria tes (sex and age) in both the major gene component and the multifactorial ( i.e., polygenic and familial environment) component. Results: Both a major effect and a multifactorial effect were significant. The percentage of the total variance accounted for by the multifactorial ef fect was 17%-24% (increasing as a function of age), and by the major effect , 8%-34% (decreasing as a function of age). Although tests on the transmiss ion probabilities (78) were not compatible with Mendelian expectations of 1 , 1/2, and 0, the equal tau s model was rejected (i.e., the effect is trans mitted in families) and the point estimates (0.96, 0.60, and 0.17) compared favorably to Mendelian expectations. The major effect was transmitted in a codominant fashion, consistent with a gene-environment interaction. Discussion: These results suggest both multifactorial and major effect etio logies for BMI in these families of extremely obese probands. Before 20 yea rs of age, the major effect dominates the BMI expression, but after age 20, multifactorial effects account for the most variance. Although the major e ffect is transmitted in these families, the pattern does not appear to be c onsistent with a simple Mendelian trait. The possibility of additional majo r loci (i.e., epistasis) and gene by environment interactions may explain t hese findings.