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 betaindirect 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.