AbstractAlthough bi-directional relationships between high body mass index (BMI) and affective symptoms have been found, no study has investigated the relationships across the life course. There has also been little exploration of whether the fat mass and obesity-associated (FTO) rs9939609 single-nucleotide polymorphism (SNP) is associated with affective symptoms and/or modifies the relationship between BMI and affective symptoms. In the MRC National Survey of Health and Development (NSHD), 4556 participants had at least one measure of BMI and affective symptoms between ages 11 and 60–64 years. A structural equation modelling framework was used with the BMI trajectory fitted as latent variables representing BMI at 11, and adolescent (11–20 years), early adulthood (20–36 years) and midlife (36–53 years) change in BMI. Higher levels of adolescent emotional problems were associated with greater increases in adult BMI and greater increases in early adulthood BMI were associated with higher subsequent levels of affective symptoms in women. The rs9939609 risk variant (A allele) from 2469 participants with DNA genotyping at age 53 years showed mostly protective effect modification of these relationship. Increases in adolescent and early adulthood BMI were generally not associated with, or were associated with lower levels, of affective symptoms in the FTO risk homozygote (AA) group, but positive associations were seen in the TT group. These results suggest bi-directional relationships between higher BMI and affective symptoms across the life course in women, and that the relationship could be ameliorated by rs9939609 risk variant.