Independent associations of TOMM40 and APOE variants with body mass index

The TOMM40-APOE variants are known for their strong, antagonistic associations with Alzheimer's disease and body weight. While a stronger role of the APOE than TOMM40 variants in Alzheimer's disease was suggested, comparative contribution of the TOMM40-APOE variants in the regulation of body weight remains elusive. We examined additive effects of rs2075650 and rs157580 TOMM40 variants and rs429358 and rs7412 APOE variants coding the ε2/ε3/ε4 polymorphism on body mass index (BMI) in age-aggregated and age-stratified cohort-specific and cohort-pooled analysis of 27,863 Caucasians aged 20-100 years from seven longitudinal studies. Minor alleles of rs2075650, rs429358, and rs7412 were individually associated with BMI (β = -1.29, p = 3.97 × 10^-9 ; β = -1.38, p = 2.78 × 10^-10 ; and β = 0.58, p = 3.04 × 10^-2 , respectively). Conditional analysis with rs2075650 and rs429358 identified independent BMI-lowering associations for minor alleles (β = -0.63, p = 3.99 × 10^-2 and β = -0.94, p = 2.17 × 10^-3 , respectively). Polygenic mega-analysis identified additive effects of the rs2075650 and rs429358 heterozygotes (β = -1.68, p = 3.00 × 10^-9 ), and the strongest BMI-lowering association for the rs2075650 heterozygous and rs429358 minor allele homozygous carriers (β = -4.11, p = 2.78 × 10^-3 ). Conditional analysis with four polymorphisms identified independent BMI-lowering (rs2075650, rs157580, and rs429358) and BMI-increasing (rs7412) associations of heterozygous genotypes with BMI. Age-stratified conditional analysis revealed well-powered support for a differential and independent association of the rs429358 heterozygote with BMI in younger and older individuals, β = 0.58, 95% confidence interval (CI) = -1.18, 2.35, p = 5.18 × 10^-1 for 3,068 individuals aged ≤30 years and β = -4.28, CI = -5.65, -2.92, p = 7.71 × 10^-10 for 6,052 individuals aged >80 years. TOMM40 and APOE variants are independently and additively associated with BMI. The APOE ε4-coding rs429358 polymorphism is associated with BMI in older individuals but not in younger individuals.