Mediation and moderation of genetic risk of obesity through eating behaviours in two UK cohorts

Background The mechanisms underlying genetic predisposition to higher body mass index (BMI) remain unclear. Methods We hypothesized that the relationship between BMI-genetic risk score (BMI-GRS) and BMI was mediated via disinhibition, emotional eating and hunger, and moderated by flexible (but not rigid) restraint within two UK cohorts: the Genetics of Appetite Study (GATE) (n = 2101, 2010-16) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 1679, 2014-18). Eating behaviour was measured by the Adult Eating Behaviour Questionnaire and Three-Factor Eating Questionaire-51. Results The association between BMI-GRS and BMI were partially mediated by habitual, emotional and situational disinhibition in the GATE/ALSPAC meta-mediation [standardized beta(indirect) 0.04, 95% confidence interval (CI) 0.02-0.06; 0.03, 0.01-0.04; 0.03, 0.01-0.04, respectively] external hunger and internal hunger in the GATE study (0.02, 0.01-0.03; 0.01, 0.001-0.02, respectively). There was evidence of mediation by emotional over/undereating and hunger in the ALSPAC study (0.02, 0.01-0.03; 0.01, 0.001-0.02; 0.01, 0.002-0.01, respectively). Rigid or flexible restraint did not moderate the direct association between BMI-GRS and BMI, but high flexible restraint moderated the effect of disinhibition subscales on BMI (reduction of the indirect mediation by -5% to -11% in GATE/ALSPAC) and external hunger (-5%) in GATE. High rigid restraint reduced the mediation via disinhibition subscales in GATE/ALSPAC (-4% to -11%) and external hunger (-3%) in GATE. Conclusions Genetic predisposition to a higher BMI was partly explained by disinhibition and hunger in two large cohorts. Flexible/rigid restraint may play an important role in moderating the impact of predisposition to higher BMI.