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鉴定与多种组织共享遗传结构相关的骨密度基因:对 EPDR1、PKDCC 和 SPTBN1 的功能见解。

Identification of bone mineral density associated genes with shared genetic architectures across multiple tissues: Functional insights for EPDR1, PKDCC, and SPTBN1.

机构信息

Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.

出版信息

PLoS One. 2024 Apr 29;19(4):e0300535. doi: 10.1371/journal.pone.0300535. eCollection 2024.


DOI:10.1371/journal.pone.0300535
PMID:38683846
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11057974/
Abstract

Recent studies suggest a shared genetic architecture between muscle and bone, yet the underlying molecular mechanisms remain elusive. This study aims to identify the functionally annotated genes with shared genetic architecture between muscle and bone using the most up-to-date genome-wide association study (GWAS) summary statistics from bone mineral density (BMD) and fracture-related genetic variants. We employed an advanced statistical functional mapping method to investigate shared genetic architecture between muscle and bone, focusing on genes highly expressed in muscle tissue. Our analysis identified three genes, EPDR1, PKDCC, and SPTBN1, which are highly expressed in muscle tissue and previously unlinked to bone metabolism. About 90% and 85% of filtered Single-Nucleotide Polymorphisms were in the intronic and intergenic regions for the threshold at P≤5×10-8 and P≤5×10-100, respectively. EPDR1 was highly expressed in multiple tissues, including muscles, adrenal glands, blood vessels, and the thyroid. SPTBN1 was highly expressed in all 30 tissue types except blood, while PKDCC was highly expressed in all 30 tissue types except the brain, pancreas, and skin. Our study provides a framework for using GWAS findings to highlight functional evidence of crosstalk between multiple tissues based on shared genetic architecture between muscle and bone. Further research should focus on functional validation, multi-omics data integration, gene-environment interactions, and clinical relevance in musculoskeletal disorders.

摘要

最近的研究表明,肌肉和骨骼之间存在共享的遗传结构,但潜在的分子机制仍难以捉摸。本研究旨在利用最新的全基因组关联研究(GWAS)汇总统计数据,从骨密度(BMD)和与骨折相关的遗传变异中,确定肌肉和骨骼之间具有共享遗传结构的功能注释基因。我们采用了先进的统计功能映射方法,研究肌肉和骨骼之间的共享遗传结构,重点关注在肌肉组织中高度表达的基因。我们的分析确定了三个基因,EPDR1、PKDCC 和 SPTBN1,它们在肌肉组织中高度表达,以前与骨代谢无关。在阈值为 P≤5×10-8 和 P≤5×10-100 时,过滤后的单核苷酸多态性中约有 90%和 85%分别位于内含子和基因间区域。EPDR1 在包括肌肉、肾上腺、血管和甲状腺在内的多种组织中高度表达。SPTBN1 在除血液外的所有 30 种组织类型中高度表达,而 PKDCC 在除大脑、胰腺和皮肤外的所有 30 种组织类型中高度表达。我们的研究为利用 GWAS 研究结果提供了一个框架,根据肌肉和骨骼之间的共享遗传结构,突出多个组织之间相互作用的功能证据。进一步的研究应集中在功能验证、多组学数据整合、基因-环境相互作用以及肌肉骨骼疾病的临床相关性上。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/25ceaaf33cd3/pone.0300535.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/3a5481c4fffa/pone.0300535.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/37ffd3ccd0ca/pone.0300535.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/a4ba5128b429/pone.0300535.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/99e50e6ff643/pone.0300535.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/aa3c8ea52801/pone.0300535.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/81f863a4413b/pone.0300535.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/25ceaaf33cd3/pone.0300535.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/3a5481c4fffa/pone.0300535.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/37ffd3ccd0ca/pone.0300535.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/a4ba5128b429/pone.0300535.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/99e50e6ff643/pone.0300535.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/aa3c8ea52801/pone.0300535.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/81f863a4413b/pone.0300535.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85c/11057974/25ceaaf33cd3/pone.0300535.g007.jpg

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本文引用的文献

[1]
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Transl Res. 2022-5

[2]
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[3]
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Cell Mol Gastroenterol Hepatol. 2022

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CRISPR-Cas9-Mediated Genome Editing Confirms as an Effector Gene at the BMD GWAS-Implicated '' Locus.

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Front Cell Dev Biol. 2021-3-19

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