Efficient multi-phenotype genome-wide analysis identifies genetic associations for unsupervised deep-learning-derived high-dimensional brain imaging phenotypes.

Bohong Guo, Ziqian Xie, Wei He, Sheikh Muhammad Saiful Islam, Assaf Gottlieb, Han Chen, Degui Zhi
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Abstract

Brain imaging is a high-content modality that offers dense insights into the structure and pathology of the brain. Existing genetic association studies of brain imaging, typically focusing on a number of individual image-derived phenotypes (IDPs), have successfully identified many genetic loci. Previously, we have created a 128-dimensional Unsupervised Deep learning derived Imaging Phenotypes (UDIPs), and identified multiple loci from single-phenotype genome-wide association studies (GWAS) for individual UDIP dimensions, using data from the UK Biobank (UKB). However, this approach may miss genetic associations where one single nucleotide polymorphism (SNP) is moderately associated with multiple UDIP dimensions. Here, we present Joint Analysis of multi-phenotype GWAS (JAGWAS), a new tool that can efficiently calculate multivariate association statistics using single-phenotype summary statistics for hundreds of phenotypes. When applied to UDIPs of T1 and T2 brain magnetic resonance imaging (MRI) on discovery and replication cohorts from the UKB, JAGWAS identified 195/168 independently replicated genomic loci for T1/T2, 6 times more than those from the single-phenotype GWAS. The replicated loci were mapped into 555/494 genes, and 217/188 genes overlapped with the expression quantitative trait loci (eQTL) of brain tissues. Gene enrichment analysis indicated that the genes mapped are closely related to neurobiological functions. Our results suggested that multi-phenotype GWAS is a powerful approach for genetic discovery using high-dimensional UDIPs.

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脑成像是一种高内容模式,可提供对大脑结构和病理的深入了解。现有的脑成像遗传关联研究通常侧重于一些单个图像衍生表型(IDP),已成功确定了许多遗传位点。此前,我们创建了一个 128 维的无监督深度学习衍生成像表型(UDIPs),并利用英国生物库(UKB)的数据,从单个表型的全基因组关联研究(GWAS)中为单个 UDIP 维度确定了多个基因位点。然而,这种方法可能会遗漏单核苷酸多态性(SNP)与多个 UDIP 维度中度相关的遗传关联。在这里,我们介绍了多表型 GWAS 联合分析(JAGWAS),这是一种新的工具,可以利用数百种表型的单表型汇总统计有效地计算多变量关联统计。当将 JAGWAS 应用于英国脑研究中心发现队列和复制队列中 T1 和 T2 脑磁共振成像(MRI)的 UDIPs 时,JAGWAS 发现了 195/168 个独立复制的 T1/T2 基因组位点,是单表型 GWAS 的 6 倍。复制的基因座被映射到 555/494 个基因中,其中 217/188 个基因与脑组织的表达定量性状位点(eQTL)重叠。基因富集分析表明,这些基因与神经生物学功能密切相关。我们的研究结果表明,多表型 GWAS 是一种利用高维 UDIPs 发现基因的有效方法。
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