Type 2 diabetes (T2D) is a major risk factor for heart failure (HF) and has elevated incidence among individuals with HF. Since genetics and HF can independently influence T2D, collider bias may occur when T2D (i.e., collider) is controlled for by design or analysis. Thus, we conducted a genome-wide association study (GWAS) of diabetes-related HF with correction for collider bias. We first performed a GWAS of HF to identify genetic instrumental variables (GIVs) for HF and to enable bidirectional Mendelian randomization (MR) analysis between T2D and HF. We identified 61 genomic loci, significantly associated with all-cause HF in 114,275 individuals with HF and over 1.5 million controls of European ancestry. Using a two-sample bidirectional MR approach with 59 and 82 GIVs for HF and T2D, respectively, we estimated that T2D increased HF risk (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04–1.10), while HF also increased T2D risk (OR 1.60, 95% CI 1.36–1.88). Then we performed a GWAS of diabetes-related HF corrected for collider bias due to the study design of index cases. After removing the spurious association of locus due to collider bias, we identified two genome-wide significant loci close to (chromosome 4) and (chromosome 9) associated with diabetes-related HF in the Million Veteran Program and replicated the associations in the UK Biobank. Our MR findings provide strong evidence that HF increases T2D risk. As a result, collider bias leads to spurious genetic associations of diabetes-related HF, which can be effectively corrected to identify true positive loci.

中文翻译：

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糖尿病相关心力衰竭全基因组关联研究中碰撞偏差的识别和校正


2 型糖尿病 (T2D) 是心力衰竭 (HF) 的主要危险因素，并且心力衰竭患者的发病率较高。由于遗传学和 HF 可以独立影响 T2D，因此当通过设计或分析控制 T2D（即对撞机）时，可能会出现对撞机偏差。因此，我们对糖尿病相关心力衰竭进行了全基因组关联研究 (GWAS)，并校正了碰撞偏差。我们首先进行了 HF 的 GWAS，以确定 HF 的遗传工具变量 (GIV)，并实现 T2D 和 HF 之间的双向孟德尔随机化 (MR) 分析。我们在 114,275 名心力衰竭患者和超过 150 万欧洲血统对照中确定了 61 个基因组位点，这些位点与全因心力衰竭显着相关。使用双样本双向 MR 方法，分别对 HF 和 T2D 使用 59 个和 82 个 GIV，我们估计 T2D 会增加 HF 风险（比值比 [OR] 1.07，95% 置信区间 [CI] 1.04–1.10），而 HF 也会增加T2D 风险增加（OR 1.60，95% CI 1.36–1.88）。然后，我们对糖尿病相关心力衰竭进行了 GWAS，并根据索引病例的研究设计校正了碰撞偏差。在消除了由于碰撞偏差导致的基因座的虚假关联后，我们在百万退伍军人计划中确定了两个接近与糖尿病相关心力衰竭相关的（4 号染色体）和（9 号染色体）的全基因组显着基因座，并在英国生物库中复制了这些关联。我们的 MR 研究结果提供了强有力的证据，证明心力衰竭会增加 T2D 风险。因此，碰撞偏差会导致糖尿病相关心力衰竭的虚假遗传关联，可以有效纠正该关联以识别真正的阳性基因座。