SNP-by-CpG Site Interactions in ABCA7 Are Associated with Cognition in Older African Americans.

Abstract

SNPs in ABCA7 confer the largest genetic risk for Alzheimer's Disease (AD) in African Americans (AA) after APOE ε4. However, the relationship between ABCA7 and cognitive function has not been thoroughly examined. We investigated the effects of five known AD risk SNPs and 72 CpGs in ABCA7, as well as their interactions, on general cognitive function (cognition) in 634 older AA without dementia from Genetic Epidemiology Network of Arteriopathy (GENOA). Using linear mixed models, no SNP or CpG was associated with cognition after multiple testing correction, but five CpGs were nominally associated (p < 0.05). Four SNP-by-CpG interactions were associated with cognition (FDR q < 0.1). Contrast tests show that methylation is associated with cognition in some genotype groups (p < 0.05): a 1% increase at cg00135882 and cg22271697 is associated with a 0.68 SD decrease and 0.14 SD increase in cognition for those with the rs3764647 GG/AG (p = 0.004) and AA (p = 2 × 10-4) genotypes, respectively. In addition, a 1% increase at cg06169110 and cg17316918 is associated with a 0.37 SD decrease (p = 2 × 10-4) and 0.33 SD increase (p = 0.004), respectively, in cognition for those with the rs115550680 GG/AG genotype. While AD risk SNPs in ABCA7 were not associated with cognition in this sample, some have interactions with proximal methylation on cognition.