Transcriptome-wide association study and eQTL colocalization identify potentially causal genes responsible for human bone mineral density GWAS associations.
Transcriptome-wide association study and eQTL colocalization identify potentially causal genes responsible for human bone mineral density GWAS associations.
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DOI：
10.7554/elife.77285
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发表时间：
2022-11-23
期刊：
影响因子：
7.7
通讯作者：
Farber CR
中科院分区：
文献类型：
--
作者：
Al-Barghouthi BM;Rosenow WT;Du KP;Heo J;Maynard R;Mesner L;Calabrese G;Nakasone A;Senwar B;Gerstenfeld L;Larner J;Ferguson V;Ackert-Bicknell C;Morgan E;Brautigan D;Farber CR
迄今为止，人类骨矿物质密度（BMD）的全基因组关联研究（GWAS）已确定了1100多种关联。然而，确定这些研究所涉及的致病基因一直具有挑战性。转录组参考数据集和计算方法（例如全转录组关联研究（TWAS）和表达数量性状基因座（eQTL）共定位）开发的最新进展已被证明在识别GWAS关联的推定因果基因方面提供了信息。在这里，我们使用TWAS/eQTL共定位与来自基因型-组织表达（GTEx）项目的转录组数据相结合，以确定迄今为止进行的最大BMD GWAS的潜在致病基因。使用这种方法，我们使用TWAS和eQTL共定位鉴定了512个基因。这组基因富集了BMD的调节因子和骨相关生物过程的成员。为了研究我们的发现的意义，我们选择PPP 6 R3，从我们的分析中得到最强有力的支持的基因，该基因以前没有参与BMD的调节，用于进一步研究。我们观察到小鼠中Ppp 6 r3缺失降低BMD。在这项工作中，我们提供了一个更新的资源，结核病致病BMD基因，并证明PPP 6 R3是结核病致病BMD GWAS基因。这些数据增加了我们对BMD遗传学的理解，并为TWAS/共定位方法在解开复杂性状遗传学中的效用提供了进一步的证据。
Genome-wide association studies (GWASs) for bone mineral density (BMD) in humans have identified over 1100 associations to date. However, identifying causal genes implicated by such studies has been challenging. Recent advances in the development of transcriptome reference datasets and computational approaches such as transcriptome-wide association studies (TWASs) and expression quantitative trait loci (eQTL) colocalization have proven to be informative in identifying putatively causal genes underlying GWAS associations. Here, we used TWAS/eQTL colocalization in conjunction with transcriptomic data from the Genotype-Tissue Expression (GTEx) project to identify potentially causal genes for the largest BMD GWAS performed to date. Using this approach, we identified 512 genes as significant using both TWAS and eQTL colocalization. This set of genes was enriched for regulators of BMD and members of bone relevant biological processes. To investigate the significance of our findings, we selected PPP6R3, the gene with the strongest support from our analysis which was not previously implicated in the regulation of BMD, for further investigation. We observed that Ppp6r3 deletion in mice decreased BMD. In this work, we provide an updated resource of putatively causal BMD genes and demonstrate that PPP6R3 is a putatively causal BMD GWAS gene. These data increase our understanding of the genetics of BMD and provide further evidence for the utility of combined TWAS/colocalization approaches in untangling the genetics of complex traits.
影响因子：
6.2
作者：
Beamer, Wesley G.;Shultz, Kathryn L.;Coombs, Harold F., III;DeMambro, Victoria E.;Reinholdt, Laura G.;Ackert-Bicknell, Cheryl L.;Canalis, Ernesto;Rosen, Clifford J.;Donahue, Leah Rae
通讯作者：
Donahue, Leah Rae
影响因子：
4.2
作者：
Brixen, K.;Beckers, S.;Peeters, A.;Piters, E.;Balemans, W.;Nielsen, T. L.;Wraae, K.;Bathum, L.;Brasen, C.;Hagen, C.;Andersen, M.;Van Hul, W.;Abrahamsen, B.
通讯作者：
Abrahamsen, B.