Epidemiological studies report beneficial associations of higher educational attainment (EDU) with Alzheimer’s disease (AD). Prior genome-wide association studies (GWAS) also reported variants associated with AD and EDU separately. The analysis of pleiotropic associations with these phenotypes may shed light on EDU-related protection against AD. We performed pleiotropic meta-analyses using Fisher’s method and omnibus test applied to summary statistics for single nucleotide polymorphisms (SNPs) associated with AD and EDU in large-scale univariate GWAS at suggestive-effect (5 × 10⁻⁸ < p < 0.1) and genome-wide (p ≤ 5 × 10⁻⁸) significance levels. We report 53 SNPs that attained p ≤ 5 × 10⁻⁸ at least in one of the pleiotropic meta-analyses and were reported in the univariate GWAS at 5 × 10⁻⁸ < p < 0.1. Of them, there were 46 pleiotropic SNPs according to Fisher’s method. Additionally, Fisher’s method identified 25 of 206 SNPs with pleiotropic effects, which attained p ≤ 5 × 10⁻⁸ in the univariate GWAS. We showed that a large fraction of the pleiotropic associations was affected by a counterintuitive phenomenon of antagonistic genetic heterogeneity, which explains the increase, rather than decrease, of the significance of the pleiotropic associations in the omnibus test. Functional enrichment analysis showed that apart from cancers, gene set harboring the non-pleiotropic SNPs was characterized by late-onset AD and neurodevelopmental disorders. The pleiotropic gene set was characterized by a broad spectrum of progressive neurological and neuromuscular diseases and immune-mediated conditions, including progressive motor neuropathy, multiple sclerosis, Parkinson’s disease, and severe AD. Our results suggest that disentangling genes harboring variants with and without pleiotropic associations with AD and EDU is promising for dissecting heterogeneity in biological mechanisms of AD.

流行病学研究报告称，高等教育程度 (EDU) 与阿尔茨海默病 (AD) 存在有益关联。之前的全基因组关联研究 (GWAS) 也分别报告了与 AD 和 EDU 相关的变异。对这些表型的多效性关联的分析可能有助于了解 EDU 相关的 AD 保护作用。我们使用 Fisher 方法和综合检验进行了多效性荟萃分析，应用于大规模单变量 GWAS 中与 AD 和 EDU 相关的单核苷酸多态性 (SNP) 的汇总统计，提示效果 (5 × 10 −8 < p ^< 0.1 )和全基因组 ( p ≤ 5 × 10 ^-8 ) 显着性水平。我们报告了 53 个 SNP，它们至少在一项多效性荟萃分析中达到了p ≤ 5 × 10 ^{-8 ，并且在单变量 GWAS 中报告为 5 × 10 -8} < p < 0.1。根据Fisher方法，其中有46个多效性SNP。此外，Fisher 方法鉴定了 206 个 SNP 中的 25 个具有多效性，在单变量 GWAS 中达到p ≤ 5 × 10 ^{-8 。}我们表明，很大一部分多效性关联受到拮抗遗传异质性的反直觉现象的影响，这解释了综合测试中多效性关联的显着性增加而不是减少。功能富集分析表明，除了癌症之外，含有非多效性 SNP 的基因集还具有迟发性 AD 和神经发育障碍的特征。多效性基因集的特点是广泛的进行性神经和神经肌肉疾病以及免疫介导的疾病，包括进行性运动神经病、多发性硬化症、帕金森病和严重的 AD。我们的结果表明，解开含有与 AD 和 EDU 多效性相关或不具有多效性关联的变异基因，有望剖析 AD 生物学机制的异质性。