Mendelian randomization shows sex-specific associations between long-chain PUFA-related genotypes and cognitive performance in Danish schoolchildren.

Dietary and endogenously formed long-chain polyunsaturated fatty acids (LCPUFAs) are hypothesized to improve cognitive development, but results are inconclusive, with suggestions of sex specificity. One study suggested that single-nucleotide polymorphisms (SNPs) rs1535 and rs174448 in the fatty acid desaturase () gene cluster have opposite effects on erythrocyte LCPUFAs at 9 mo. To explore whether SNPs in and elongase () genes were associated with school performance in a sex-specific manner, we performed a Mendelian randomization study using data from the Optimal well-being, development and health for Danish children through a healthy New Nordic Diet (OPUS) School Meal Study with 765 Danish schoolchildren 8-11 y old. Associations between selected SNPs (rs1535, rs174448, and rs174468) and rs2397142, whole-blood fatty acid composition, and performance in the d2 Test of Attention and a reading test were analyzed in multiple regression models including all SNPs, SNP-sex interactions, and covariates related to testing conditions., rs1535 minor allele carriage associated with lower whole-blood arachidonic acid ( ≤ 0.002), and minor alleles of rs174448 tended to associate with lower docosahexaenoic acid (DHA) ( = 0.052). We identified sex interactions in 50% of the SNP performance sets. Sex-dependent associations were observed for rs174448 and rs1535 on the d2 Test of Attention outcomes ( < 0.03) and for the associations between reading scores and rs174448 and rs2397142 ( < 0.01). All of the sex-specific analyses showed associations in opposite directions in girls and boys. The minor allele carriage of rs174448 was associated with lower d2 Test of Attention performance ( < 0.02) and reading scores ( < 0.001) in boys but with better reading scores in girls ( ≤ 0.002). The associations were consistently the opposite for rs1535 minor allele carriage ( < 0.05). Associations with rs2397142 also appeared to be opposite of those of rs174448, but only for reading and not significant after adjustment for parental educational level and whole-blood DHA. This study showed associations between rs1535 minor allele homozygosity and rs174448 major allele carriage and improved performance in 8- to 11-y-old boys but not in girls, thereby counteracting existing sex differences. This may be a consequence of increased endogenous DHA synthesis in infancy but not at school-age. This trial was registered at clinicaltrials.gov as NCT01457794.