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

Abstract

Background: Accumulating evidence suggests that breastfeeding benefits children's intelligence, possibly due to long-chain polyunsaturated fatty acids (LC-PUFAs) present in breast milk. 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: We investigated this gene × environment interaction through a collaborative effort. The primary analysis involved >12 000 individuals and used ever breastfeeding, FADS2 polymorphisms rs174575 and rs1535 coded assuming a recessive effect of the G allele, and intelligence quotient (IQ) in Z scores.

Results: 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% confidence interval (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.

Conclusions: Our findings did not support an interaction between ever breastfeeding and FADS2 polymorphisms. However, subgroup analysis suggested that breastfeeding may supply LC-PUFAs requirements for cognitive development if breastfeeding lasts for some (currently unknown) time. Future studies in large individual-level datasets would allow properly powered subgroup analyses and further improve our understanding on the breastfeeding × FADS2 interaction.

Keywords: Breastfeeding; FADS2; effect modification; fatty acids; intelligence; meta-analysis.

Figure 1.

Illustration of the nutritional adequacy hypothesis involving breastfeeding, LC-PUFAs levels and associated genotypes, and cognitive development. Left panel: the benefits of increasing LC-PUFAs on cognitive development are assumed to exist only until a given level of LC-PUFAs (marked by T). Further increasing LC-PUFAs above T brings no further cognitive benefits. Right panel: breastfeeding is assumed to provide LC-PUFA levels above T regardless of genetic predisposition to higher or lower endogenous synthesis of LC-PUFAs. Non-breastfed individuals are assumed to need such genetic load of higher endogenous synthesis to achieve T. LC-PUFAs: long-chain polyunsaturated fatty acids.

Figure 2.

Forest plots of the G × E interaction coefficients^a from the fully-adjusted^b primary analysis (FADS2 variants coded in recessive form, and breastfeeding categorized into ever x never breastfeeding) based on random effects meta-analysis. SKOT-I and SKOT-II were excluded from the analyses for the rs174575 polymorphism because the model did not fit (due to a combination of modest sample size, high prevalence of breastfeeding and assuming a recessive genetic effect of the rarest allele). 1982Pelotas, 1982 Pelotas Birth Cohort; ALSPAC, Avon Longitudinal Study of Parents and Children; COPSAC2010, Copenhagen Prospective Study on Asthma in Childhood 2010; DMHDS, Dunedin Multidisciplinary Health and Development Study; GenerationR, Generation R Study; INMA, INfancia y Medio Ambiente [Environment and Childhood]; Raine, Western Australian Pregnancy Cohort (Raine) Study; SKOT-I and II, Småbørn Kost Og Trivsel (I and II); SYS, Saguenay Youth Study. ^aThese coefficients can be interpreted as the mean difference in IQ Z scores comparing ever with never breastfed individuals among GG carriers minus the mean difference in IQ Z scores comparing ever with never breastfed individuals among carriers of other genotypes. ^bCovariates were sex, age (linear and quadratic terms), ancestry-informative principal components (if available), genotyping centre (if necessary), maternal education (linear and quadratic terms) and/or maternal cognition (linear and quadratic terms).