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

Background: DHA accretes in the brain during the growth spurt, but results regarding a potential programming effect on cognitive function and behavior in humans are inconclusive. DHA can be supplied by the diet or synthesized from α-linoleic acid, and the biosynthetic capacity is modified by single nucleotide polymorphisms (SNPs) in the FADS-gene cluster.Objective: To investigate if behavioral outcomes in childhood were associated with three FADS tag-SNPs previously found to have opposing and allele number-dependent effects on infant erythrocyte DHA. Minor allele carriers of rs1535 had increased DHA, whereas those with minor alleles of rs174448 and rs174575 had decreased DHA (effect size around 0.5%-point per allele).Design: At 36 months we assessed psychomotor development by the Ages & Stages Questionnaire (n258) and physical activity by accelerometric recordings (n=231) in children from the SKOT cohort. Blood samples were taken to determine erythrocyte DHA-status (n=192) and the three FADS tag-SNPs (n=255). All outcomes were analyzed using multiple regression models including the three SNPs, SNP-gender interactions, and adjustment for parental education, siblings, birth-weight, and duration of breastfeeding as well as by gender-specific analysis if indicated by interactions.Results: SNP-gender interactions were found for both communication and problem solving (p=0.008-0.025). Relative to wild type individuals female rs174448 heterozygotes had better communication (=4.895%CI: 0.7;9.0) and problem solving (4.70.6;8.8), whereas the associations were negative in boys (-4.9-8.9;-1.0 and -2.0-5.7;1.7, respectively). Similar results were seen for rs174575 and communication, but all associations for rs1535 were in the opposite direction (communication: boys 6.30.4;12.3 and girls: -5.2-10.7;0.2 and for problem solving most pronounced in homozygotes (boys=11.9-0.6;24.3 and girls=-8.7-17.1;-0.2). Some associations were also seen for fine motor development, but none for physical activity.Conclusion: FADS SNPs seem to have an independent and gender-specific effect on behavior in children, possibly indicating a programming effect of early DHA exposure.