A Genome-Wide Interaction Study of Erythrocyte ω-3 Polyunsaturated Fatty Acid Species and Memory in the Framingham Heart Study Offspring Cohort

Background: Cognitive decline, and more speci fi cally Alzheimer ' s disease, continues to increase in prevalence globally, with few, if any, adequate preventative approaches. Several tests of cognition are utilized in the diagnosis of cognitive decline that assess executive function, short- and long-term memory, cognitive fl exibility, and speech and motor control. Recent studies have separately investigated the genetic component of both cognitive health, using these measures, and circulating fatty acids. Objectives: We aimed to examine the potential moderating effect of main species of co -3 polyunsaturated fatty acids (PUFAs) on an individual ' s genetically conferred risk of cognitive decline. Methods: The Offspring cohort from the Framingham Heart Study was cross -sectionally analyzed in this genome-wide interaction study (GWIS). Our sample included all individuals with red blood cell co -3 PUFA, genetic, cognitive testing (via Trail Making Tests [TMTs]), and covariate data ( N = 1620). We used linear mixed effects models to predict each of the 3 cognitive measures (TMT A, TMT B, and TMT D) by each co -3 PUFA, single nucleotide polymorphism (SNP) (0, 1, or 2 minor alleles), co -3 PUFA by SNP interaction term, and adjusting for sex, age, education, APOE e 4 genotype status, and kinship (relatedness). Results: Our analysis identi fi ed 31 unique SNPs from 24 genes reaching an exploratory signi fi cance threshold of 1 x 10 -5 . Fourteen of the 24 genes have been previously associated with the brain/cognition, and 5 genes have been previously associated with circulating lipids. Importantly, 8 of the genes we identi fi ed, DAB1 , SORCS2 , SERINC5 , OSBPL3 , CPA6 , DLG2 , MUC19 , and RGMA , have been associated with both cognition and circulating lipids. We identi fi ed 22 unique SNPs for which individuals with the minor alleles bene fi t substantially from increased co -3 fatty acid concentrations and 9 unique SNPs for which the common homozygote bene fi ts. Conclusions: In this GWIS of co -3 PUFA species on cognitive outcomes, we identi fi ed 8 unique genes with plausible biology suggesting individuals with speci fi c polymorphisms may have greater potential to bene fi t from increased co -3 PUFA intake. Additional replication in prospective settings with more diverse samples is needed.