FADS single-nucleotide polymorphisms are associated with behavioral outcomes in children, and the effect varies between sexes and is dependent on PPAR genotype.

BACKGROUND Docosahexaenoic acid (DHA), supplied by the diet or endogenous biosynthesis from α-linolenic acid, accretes during the perinatal brain growth spurt. Results regarding a potential programming effect on cognitive function and behavior in humans are inconclusive. OBJECTIVE Here we aimed to investigate whether behavioral outcomes in childhood were associated with FADS tag-single-nucleotide polymorphisms (SNPs) previously found to have opposing effects on infant erythrocyte DHA. DESIGN At 36 mo, we assessed psychomotor development with the third edition of the Ages & Stages Questionnaire (n = 256) and physical activity by accelerometry (n = 231) in children from the SKOT [Småbørns Kost Og Trivsel (Diet and Thriving in Young Children)] cohort. Blood samples were taken to determine erythrocyte DHA (n = 200), FADS tag-SNPs (n = 255), and PPARG-Pro12Ala (n = 255). All outcomes were analyzed in models, including all 3 SNPs, SNP-sex interactions, erythrocyte DHA at 36 mo, and covariates. RESULTS As previously shown, the minor allele carriers of the FADS SNP rs1535 had increased erythrocyte DHA at 9 mo, whereas DHA decreased in minor allele carriers of rs174448 and rs174575 (effect size around 0.5 percentage points per allele). No overall effects were observed for any of the FADS SNPs on the outcomes reported here, but FADS SNP-sex interactions were found for a number of DHA-increasing FADS alleles on both communication and problem solving (P = 0.005 and 0.013). DHA-increasing FADS alleles resulted in reduced scores in girls and improved abilities in boys, with an effect size of ∼1 score-point/allele. No associations were found between current erythrocyte DHA and any of the behavioral outcomes. The P value for the triple interaction between DHA-increasing FADS alleles, PPARG, and sex for communication was 0.051, and subsequent analyses showed the FADS-sex interaction only in PPARG minor allele carriers (n = 70). Furthermore, FADS-PPARG interactions were seen for problem solving in boys and for fine motor skills in girls. CONCLUSION FADS SNPs seem to have a sex-specific, possibly peroxisome proliferator-activated receptor-mediated effect on behavior in children, indicating a programming effect of early DHA exposure.