The APOE ε2/ε3/ε4 polymorphism is associated with multiple non-Mendelian traits, including high- (HDL-C) and low- (LDL-C) density lipoprotein cholesterol, triglycerides, body mass index (BMI), coronary heart disease (CHD), and Alzheimer’s disease (AD). Lipids and BMI are risk factors for AD and CHD. Causal connections between the ε2 and ε4 alleles and these traits remain, however, poorly understood. We leverage comprehensive analyses of longitudinal data from four studies to examine potentially causal heterogeneous connections between these alleles, lipids, BMI, and diseases. We emphasize mutual mediation roles of lipids and BMI in their associations with the ε2 and ε4 alleles and their mediation roles in the associations of these alleles with AD and CHD. We confirmed previously reported significant univariate associations of these alleles with each trait, except CHD. We found, however, that most of the univariate- and mediation-analysis associations were affected by antagonistic heterogeneity/mediation. The mutual mediation analysis identified the associations of the APOE alleles with LDL-C as the least heterogeneous. The ε2 and ε4 alleles were associated with CHD through lipids, led by beneficial (β_IE = − 0.071, p_IE = 2.28 × 10⁻¹⁰) and adverse (β_IE = 0.019, p_IE = 7.37 × 10⁻⁶) associations, respectively, through LDL-C. Both these alleles were adversely associated with CHD through triglycerides. For AD, only BMI partially mediated the adverse association of the ε4 allele with AD (β_IE = 0.016, p_IE = 2.09 × 10⁻²). Our results suggest different roles of BMI and lipids in the AD and CHD pathogeneses. More comprehensive studies of causal connections between genetic variants and non-Mendelian traits are required as they can be critically affected by heterogeneous antagonistic relationships.

APOE _ε2/ε3/ε4 多态性与多种非孟德尔性状相关，包括高 (HDL-C) 和低 (LDL-C) 密度脂蛋白胆固醇、甘油三酯、体重指数 (BMI)、冠心病 (CHD)和阿尔茨海默病 (AD)。血脂和 BMI 是 AD 和 CHD 的危险因素。然而，ε2 和 ε4 等位基因与这些特征之间的因果关系仍然知之甚少。我们利用来自四项研究的纵向数据的综合分析来检查这些等位基因、脂质、BMI 和疾病之间潜在的因果异质联系。我们强调脂质和 BMI 在它们与 ε2 和 ε4 等位基因的关联中的相互中介作用，以及它们在这些等位基因与 AD 和 CHD 的关联中的中介作用。我们证实了先前报道的这些等位基因与每个性状的显着单变量关联，除了冠心病。然而，我们发现，大多数单变量和中介分析关联都受到拮抗异质性/中介的影响。相互中介分析确定了以 LDL-C 为异质性最低的APOE等位基因。ε2 和 ε4 等位基因通过脂质与 CHD 相关，由有益（β _IE  = - 0.071，p _IE  = 2.28 × 10 ^-10）和不利（β _IE  = 0.019，p _IE  = 7.37 × 10 ^-6）关联主导，分别通过 LDL-C。这两个等位基因都通过甘油三酯与冠心病呈负相关。对于 AD，只有 BMI 部分介导了 ε4 等位基因与 AD 的不良关联（β _IE  = 0.016，p _IE  = 2.09 × 10 ^-2）。我们的结果表明 BMI 和脂质在 AD 和 CHD 发病机制中的不同作用。需要对遗传变异和非孟德尔性状之间的因果关系进行更全面的研究，因为它们可能受到异质对抗关系的严重影响。