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PgmNr 2873: Genetic factors that modulate the relationship between education and Alzheimer's disease.

Authors:
R.A. Bhatta 1; S.-Y. Chou 2,3; Y. Zhao 1; L. Qu 1; A. Kuzma 1; G. Schellenberg 1; L.-S. Wang 1

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Affiliations:
1) Penn Neurodegeneration Genomics Center, Dept of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 2) Dept of Economics, Lehigh University, Bethlehem, PA; 3) National Bureau of Economic Research, Cambridge, MA


Neither genetics nor environmental factors alone fully explains observed phenotypic variation in Alzheimer’s disease (AD), suggesting a possible role for gene-environment interactions in the etiology of AD. The purpose of this study is to examine one environmental factor implicated to have a protective effect against AD: education. Specifically, using known genetic risk/protective factors for AD, we consider how gene-education interactions relate to AD risk.

Using phenotype data from National Alzheimer’s Disease Coordinating Center (NACC) and HRC imputation data from Alzheimer’s Disease Genetics Consortium (ADGC), we employ a regression approach utilizing linear probability models. All models control for sex, race/ethnicity, APOE, APOE interacted with sex, age at first visit, genotyping cohort, and study recruitment site. Standard errors are clustered by recruitment site, allowing for within-site error correlation. In the first step of our analysis, we interact the top genome-wide significant AD single nucleotide polymorphisms (SNPs) (see Lambert et al., 2013) with indicator variables for education level. The main outcome variable, the likelihood of AD, is regressed on these interaction terms and all control variables. Any statistically significant SNP-education interactions are used for localized analysis in the second step, in which we incorporate all SNPs located within close proximity of this 'top' significant SNP.

Results from the first step identify a nominally significant, negative interaction between education and rs2718058 (7:37841534), a SNP located near the NME8 gene. The negative coefficient estimates indicate that higher educated groups possessing a greater number of minor alleles are less likely to develop AD when compared to the least educated group, i.e. the effect of education is amplified by the minor (in this case, protective) allele. Upon closer examination of neighboring SNPs, located within ~300Kbp of this top SNP, we discover both positive and negative interactions with education. These localized results suggest the possibility of at least three haplotypes conferring interaction effects with education level.

Further analyses will exploit advanced econometric techniques as well as Mendelian Randomization for causal inference on the relationship between education and AD.