Aims: The FADS1/FADS2 gene cluster encodes Δ-5 and Δ-6 desaturase, rate-limiting enzymes in metabolism of linoleic (LA) to arachidonic (ARA) and α-linolenic to eicosapentaenoic and docosahexaenoic acid (DHA). Single nucleotide polymorphisms (SNPs) in FADS1/FADS2 contribute to variability in blood lipid fatty acids. Altered n–6 and n–3 fatty acids have been related to perinatal depression (PPD). Methods: We genotyped rs174553, rs99780, rs174575, and rs174583 in FADS1/FADS2, analyzed blood lipid fatty acids and assessed PPD risk as an Edinburgh Postnatal Depression Scale (EPDS) score ≧10 for 69 pregnant women. Results: 21, 12 and 15% women had an EPDS score ≧10 at 36 weeks’ gestation, 2 and 6 months postpartum, respectively. Quantitative trait analysis showed an association between rs174575 and PPD risk at 36 weeks’ gestation and 6 months postpartum. With haplotype ACCC (major alleles) for rs174553, rs99780, rs174575, rs174583, respectively, as reference, GTCT was positively associated with PPD risk at 36 weeks’ gestation, p = 0.028, and higher LA and lower ARA in plasma (p = 0.0001, p < 0.0001) and RBC ethanolamine phospholipids (p = 0.007, p = 0.005). Conclusions: We show that SNPs in FADS1/FADS2 are associated with higher blood lipid LA and lower ARA and PPD risk.

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