Abstract
OBJECTIVE: To determine the putative protective relationship of educational attainment on Alzheimer disease (AD) risk using Mendelian randomization and to test the hypothesis that by using genetic regions surrounding individually associated single nucleotide polymorphisms (SNPs) as the instrumental variable, we can identify genes that contribute to the relationship. METHODS: We performed Mendelian randomization using genome-wide association study summary statistics from studies of educational attainment and AD in two stages. Our instrumental variable comprised (1) 1,271 SNPs significantly associated with educational attainment and (2) individual 2-Mb regions surrounding the genome-wide significant SNPs. RESULTS: A causal inverse relationship between educational attainment and AD was identified by the 1,271 SNPs (odds ratio = 0.63; 95% confidence interval, 0.54-0.74; p = 4.08 x 10(-8)). Analysis of individual loci identified 2 regions that significantly replicated the causal relationship. Genes within these regions included LRRC2, SSBP2, and NEGR1; the latter a regulator of neuronal growth. CONCLUSIONS: Educational attainment is an important protective factor for AD. Genomic regions that significantly paralleled the overall causal relationship contain genes expressed in neurons or involved in the regulation of neuronal development.