Transcriptome-wide association studies (TWASs) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans-expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian genome-wide TWAS (BGW-TWAS) method that leverages both cis- and trans-eQTL information for a TWAS. Our BGW-TWAS method is based on Bayesian variable selection regression, which not only accounts for cis- and trans-eQTL of the target gene but also enables efficient computation by using summary statistics from standard eQTL analyses. Our simulation studies illustrated that BGW-TWASs achieved higher power compared to existing TWAS methods that do not assess trans-eQTL information. We further applied BWG-TWAS to individual-level GWAS data (N = ∼3.3K), which identified significant associations between the genetically regulated gene expression (GReX) of ZC3H12B and Alzheimer dementia (AD) (p value = 5.42 × 10⁻¹³), neurofibrillary tangle density (p value = 1.89 × 10⁻⁶), and global measure of AD pathology (p value = 9.59 × 10⁻⁷). These associations for ZC3H12B were completely driven by trans-eQTL. Additionally, the GReX of KCTD12 was found to be significantly associated with $\mathit{\beta }$-amyloid (p value = 3.44 × 10⁻⁸) which was driven by both cis- and trans-eQTL. Four of the top driven trans-eQTL of ZC3H12B are located within APOC1, a known major risk gene of AD and blood lipids. Additionally, by applying BGW-TWAS with summary-level GWAS data of AD (N = ∼54K), we identified 13 significant genes including known GWAS risk genes HLA-DRB1 and APOC1, as well as ZC3H12B.

全转录组关联研究（TWAS）已被广泛用于整合基因表达和遗传数据以研究复杂性状。由于计算负担，现有的 TWAS 方法不评估已知解释大多数基因的重要表达变异的远距离反式表达数量性状基因座（eQTL）。我们提出了一种贝叶斯全基因组 TWAS (BGW-TWAS) 方法，该方法利用顺式和反式eQTL 信息进行 TWAS。我们的 BGW-TWAS 方法基于贝叶斯变量选择回归，不仅考虑了目标基因的顺式和反式eQTL，而且还可以通过使用标准 eQTL 分析的汇总统计数据实现高效计算。我们的模拟研究表明，与不评估反式eQTL 信息的现有 TWAS 方法相比，BGW-TWAS 获得了更高的功效。我们进一步将 BWG-TWAS 应用于个体水平 GWAS 数据 (N = ∼3.3K)，该数据确定了ZC3H12B的遗传调控基因表达 (GReX) 与阿尔茨海默氏痴呆 (AD) 之间的显着关联（p 值 = 5.42 × 10 ^-13 ）、神经原纤维缠结密度（p 值 = 1.89 × 10 ^-6 ）和 AD 病理的整体测量（p 值 = 9.59 × 10 ^-7 ）。 ZC3H12B的这些关联完全由反式eQTL 驱动。此外， KCTD12的 GReX 被发现与-淀粉样蛋白（p 值 = 3.44 × 10 ^-8 ），由顺式和反式eQTL 驱动。 ZC3H12B的四个顶部驱动的反式eQTL 位于APOC1内，APOC1 是已知的 AD 和血脂的主要风险基因。此外，通过应用 BGW-TWAS 和 AD 的汇总级 GWAS 数据（N = ∼54K），我们鉴定了 13 个重要基因，包括已知的 GWAS 风险基因HLA-DRB1和APOC1以​​及ZC3H12B。