Preprint open access publication

Effect modification of FADS2 polymorphisms on the association between breastfeeding and intelligence: results from a collaborative meta-analysis

bioRxiv, Cold Spring Harbor Laboratory,


DOI:10.1101/184234, Dimensions: pub.1091916837,



  1. (1) University of Bristol, grid.5337.2
  2. (2) Federal University of Pelotas, grid.411221.5
  3. (3) COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
  4. (4) Duke University, grid.26009.3d
  5. (5) King's College London, grid.13097.3c
  6. (6) University of Otago, grid.29980.3a
  7. (7) Erasmus University Medical Center, grid.5645.2
  8. (8) ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
  9. (9) Pompeu Fabra University, grid.5612.0
  10. (10) Institute of Health Carlos III, grid.413448.e
  11. (11) Centre for Genomic Regulation, grid.11478.3b
  12. (12) Biodonostia, grid.432380.e
  13. (13) Public Health Division of Gipuzkoa, San Sebastian, Spain
  14. (14) University of Toronto, grid.17063.33
  15. (15) Hospital for Sick Children, grid.42327.30
  16. (16) University of Copenhagen, grid.5254.6, KU
  17. (17) University of Tasmania, grid.1009.8
  18. (18) University of Western Australia, grid.1012.2
  19. (19) University of Queensland, grid.1003.2


Abstract 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 Gene×Environment 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 IQZ 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 breastfeeding× FADS2 interaction.

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