Almost every recent Alzheimer’s disease (AD) genome-wide association study (GWAS) has performed meta-analysis to combine studies with clinical diagnosis of AD with studies that use proxy phenotypes based on parental disease history. Here, we report major limitations in current GWAS-by-proxy (GWAX) practices due to uncorrected survival bias and nonrandom participation in parental illness surveys, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that the current AD GWAX provide highly misleading genetic correlations between AD risk and higher education, which subsequently affects a variety of genetic epidemiological applications involving AD and cognition. Our study sheds light on potential issues in the design and analysis of middle-aged biobank cohorts and underscores the need for caution when interpreting genetic association results based on proxy-reported parental disease history.

几乎所有最近的阿尔茨海默病 （AD） 全基因组关联研究 （GWAS） 都进行了荟萃分析，将 AD 临床诊断的研究与使用基于父母疾病史的代理表型的研究相结合。在这里，我们报告了当前 GWAS-by-proxy （GWAX） 实践的主要局限性，这是由于未纠正的生存偏倚和非随机参与父母疾病调查，这导致 AD GWAS 和 GWAX 结果之间存在很大差异。我们证明，当前的 AD GWAX 在 AD 风险和高等教育之间提供了高度误导性的遗传相关性，这随后影响了涉及 AD 和认知的各种遗传流行病学应用。我们的研究揭示了中年生物样本库队列设计和分析中的潜在问题，并强调了在根据代理报告的父母疾病史解释遗传关联结果时需要谨慎。