Abstract
Objective To determine the putative protective relationship of educational attainment on Alzheimer’s disease (AD) risk using Mendelian randomization, and to test the hypothesis that by using genetic regions surrounding individually associated 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 of i) 1,271 SNPs significantly associated with educational attainment and ii) individual 2Mb 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% CI, 0.54-0.74; p =4.08×10−8). Analysis of individual loci identified six 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.
Contributions
All authors of the study: Neha Raghavan, Badri Vardarajan, Richard Mayeux, contributed to the study design, study analysis and writing and editing.
Acknowledgements
Support for this work was provided by grants from the National Institute on Aging from the National Institutes of Health (U01AG032984 and RO1AG041797) and the National Center for Advancing Translational Sciences (TL1TR001875). We thank the International Genomics of Alzheimer’s Project and Lee et al. for providing summary statistics for this project.
Footnotes
Study Funding: National Institute on Aging from the National Institutes of Health (U01AG032984 and RO1AG041797) and the National Center for Advancing Translational Sciences (TL1TR001875)
Disclosure of financial interests: All authors have no financial relationships relevant to the manuscript to disclose.