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Background: Accumulating evidence suggests that breastfeeding benefits the children's intelligence. Long-chain polyunsaturated fatty acids (LC-PUFAs) present in breast milk may explain part of this association. Under a nutritional adequacy hypothesis, an interaction between breastfeeding and genetic variants associated with endogenous LC-PUFAs synthesis might be expected. However, the literature on this topic is controversial. Methods and Findings: We investigated this GenexEnvironment interaction in a de novo meta-analysis involving >12,000 individuals in the primary analysis, and >45,000 individuals in a secondary analysis using relaxed inclusion criteria. Our primary analysis used ever breastfeeding, FADS2 polymorphisms rs174575 and rs1535 coded assuming a recessive effect of the G allele, and intelligence quotient (IQ) in Z scores. Using random effects meta-analysis, ever breastfeeding was associated with 0.17 (95% CI: 0.03; 0.32) higher Z scores in IQ, or about 2.1 points. There was no strong evidence of interaction, with pooled covariate-adjusted interaction coefficients (i.e., difference between genetic groups of the difference in IQ Z scores comparing ever with never breastfed individuals) of 0.12 (95% CI: -0.19; 0.43) and 0.06 (95% CI: -0.16; 0.27) for the rs174575 and rs1535 variants, respectively. Secondary analyses corroborated these results. In studies with ≥5.85 and <5.85 months of breastfeeding duration, pooled estimates for the rs174575 variant were 0.50 (95% CI: -0.06; 1.06) and 0.14 (95% CI: -0.10; 0.38), respectively, and 0.27 (95% CI: -0.28; 0.82) and -0.01 (95% CI: -0.19; 0.16) for the rs1535 variant. However, between-group comparisons were underpowered. Conclusions: Our findings do not support an interaction between ever breastfeeding and FADS2 polymorphisms. However, our subgroup analysis raises the possibility that breastfeeding supplies LC-PUFAs requirements for cognitive development (if such threshold exists) if it lasts for some (currently unknown) time. Future studies in large individual-level datasets would allow properly powered subgroup analyses and would improve our understanding on the role of breastfeeding duration in the breastfeedingxFADS2 interaction.

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