A scalable variational approach to characterize pleiotropic components across thousands of human diseases and complex traits using GWAS summary statistics.
A scalable variational approach to characterize pleiotropic components across thousands of human diseases and complex traits using GWAS summary statistics.
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一种可扩展的变分方法，使用 GWAS 摘要统计来表征数千种人类疾病和复杂性状的多效性成分。
DOI：
10.1101/2023.03.27.23287801
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Mancuso,Nicholas
中科院分区：
文献类型：
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作者：
Zhang,Zixuan;Jung,Junghyun;Kim,Artem;Suboc,Noah;Gazal,Steven;Mancuso,Nicholas
全基因组关联研究（GWAS）在数千个性状中揭示了与性状相关的遗传变异的普遍多效性。虽然已经提出了方法来表征各组表型中的多效性组分，但将这些方法扩展到超大规模生物库一直具有挑战性。在这里，我们提出了FactorGo，一个可扩展的变分因子分析模型，使用生物银行GWAS汇总数据识别和表征多效性成分。在广泛的模拟中，我们观察到FactorGo在捕获跨表型的潜在多效性因子方面优于最先进的（无模型）方法tSVD，同时保持类似的计算成本。我们应用FactorGo从欧洲血统Pan-UK BioBank个体（N= 420，531）中测量的2，483种表型的GWAS汇总数据中估计了100个潜在的多效性因子。接下来，我们发现FactorGo中的因子比tSVD确定的因子更富含相关的组织特异性注释（P=2.58E-10），并通过概括BMI的大脑特异性富集以及生殖系统与肌肉骨骼生长之间的高度相关联系来验证我们的方法。最后，我们的分析表明，除了碱性磷酸酶作为前列腺癌的候选预后生物标志物外，类风湿性关节炎和牙周病之间存在新的共同病因。总的来说，FactorGo提高了我们对数千个GWAS中共有病因的生物学理解。
Genome-wide association studies (GWAS) across thousands of traits have revealed the pervasive pleiotropy of trait-associated genetic variants. While methods have been proposed to characterize pleiotropic components across groups of phenotypes, scaling these approaches to ultra large-scale biobanks has been challenging. Here, we propose FactorGo, a scalable variational factor analysis model to identify and characterize pleiotropic components using biobank GWAS summary data. In extensive simulations, we observe that FactorGo outperforms the state-of-the-art (model-free) approach tSVD in capturing latent pleiotropic factors across phenotypes, while maintaining a similar computational cost. We apply FactorGo to estimate 100 latent pleiotropic factors from GWAS summary data of 2,483 phenotypes measured in European-ancestry Pan-UK BioBank individuals (N=420,531). Next, we find that factors from FactorGo are more enriched with relevant tissue-specific annotations than those identified by tSVD (P=2.58E-10), and validate our approach by recapitulating brain-specific enrichment for BMI and the height-related connection between reproductive system and muscular-skeletal growth. Finally, our analyses suggest novel shared etiologies between rheumatoid arthritis and periodontal condition, in addition to alkaline phosphatase as a candidate prognostic biomarker for prostate cancer. Overall, FactorGo improves our biological understanding of shared etiologies across thousands of GWAS.