Recent discoveries from large-scale genome-wide association studies (GWASs) explain a larger proportion of the genetic variability to BMI and obesity. The genetic risk associated with BMI and obesity can be assessed by an obesity-specific genetic risk score (GRS) constructed from genome-wide significant genetic variants. The aim of our study is to examine whether the duration and exclusivity of breastfeeding can attenuate BMI increase during childhood and adolescence due to genetic risks. A total sample of 5,266 children (2,690 boys and 2,576 girls) from the Avon Longitudinal Study of Parents and Children (ALSPAC) was used for the analysis. We evaluated the role of breastfeeding (exclusivity and duration) in modulating BMI increase attributed to the GRS from birth to 18 years of age. The GRS was composed of 69 variants associated with adult BMI and 25 non-overlapping SNPs associated with pediatric BMI. In the high genetic susceptible group (upper GRS quartile), exclusive breastfeeding (EBF) to 5 months reduces BMI by 1.14 kg/m 2 (95% CI, 0.37 to 1.91, p = 0.0037) in 18-year-old boys, which compensates a 3.9-decile GRS increase. In 18-year-old girls, EBF to 5 months decreases BMI by 1.53 kg/m 2 (95% CI, 0.76 to 2.29, p <0.0001), which compensates a 7.0-decile GRS increase. EBF acts early in life by delaying the age at adiposity peak and at adiposity rebound. EBF to 3 months or non-exclusive breastfeeding was associated with a significantly diminished impact on reducing BMI growth during childhood. EBF influences early life growth and development and thus may play a critical role in preventing overweight and obesity among children at high-risk due to genetic factors. Author summary Previous studies have shown that EBF is associated with lower BMI during childhood and adolescence. Moreover, a GRS based on 97 genetic variants has been derived from large GWASs and is predictive of BMI in adults and children. However, it remains unclear whether EBF can attenuate the increase in BMI attributed to the GRS in children. Our study was able to characterize the effect of the GRS in children from birth to 18 years of age. Our main results showed that EBF to 5 months has substantial effect in decreasing BMI among children at higher genetic risks. EBF to 3 months or non-exclusive breastfeeding had a significantly diminished effect on reducing BMI growth during childhood. Our study suggests that interventions aimed at reducing the risks of overweight and obesity across the lifespan should start in very early childhood to be impactful, which makes EBF a key candidate intervention. While EBF is beneficial to all children, targeting those carrying multiple BMI/obesity alleles should be a priority to reduce obesity and associated non-communicable diseases.
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