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Prioritization of Osteoporosis‐Associated Genome‐wide Association Study (GWAS) Single‐Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics

Genetic risk factors for osteoporosis, a prevalent disease associated with aging, have been examined in many genome‐wide association studies (GWASs). A major challenge is to prioritize transcription‐regulatory GWAS‐derived variants that are likely to be functional. Given the critical role of epigene...

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Autores principales: Zhang, Xiao, Deng, Hong‐Wen, Shen, Hui, Ehrlich, Melanie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101624/
https://www.ncbi.nlm.nih.gov/pubmed/33977200
http://dx.doi.org/10.1002/jbm4.10481
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author Zhang, Xiao
Deng, Hong‐Wen
Shen, Hui
Ehrlich, Melanie
author_facet Zhang, Xiao
Deng, Hong‐Wen
Shen, Hui
Ehrlich, Melanie
author_sort Zhang, Xiao
collection PubMed
description Genetic risk factors for osteoporosis, a prevalent disease associated with aging, have been examined in many genome‐wide association studies (GWASs). A major challenge is to prioritize transcription‐regulatory GWAS‐derived variants that are likely to be functional. Given the critical role of epigenetics in gene regulation, we have used an unusual epigenetics‐based and transcription‐based approach to identify some of the credible regulatory single‐nucleotide polymorphisms (SNPs) relevant to osteoporosis from 38 reported bone mineral density (BMD) GWASs. Using Roadmap databases, we prioritized SNPs based upon their overlap with strong enhancer or promoter chromatin preferentially in osteoblasts relative to 12 heterologous cell culture types. We also required that these SNPs overlap open chromatin (Deoxyribonuclease I [DNaseI]‐hypersensitive sites) and DNA sequences predicted to bind to osteoblast‐relevant transcription factors in an allele‐specific manner. From >50,000 GWAS‐derived SNPs, we identified 14 novel and credible regulatory SNPs (Tier‐1 SNPs) for osteoporosis risk. Their associated genes, BICC1, LGR4, DAAM2, NPR3, or HMGA2, are involved in osteoblastogenesis or bone homeostasis and regulate cell signaling or enhancer function. Four of these genes are preferentially expressed in osteoblasts. BICC1, LGR4, and DAAM2 play important roles in canonical Wnt signaling, a pathway critical for bone formation and repair. The transcription factors predicted to bind to the Tier‐1 SNP‐containing DNA sequences also have bone‐related functions. We present evidence that some of the Tier‐1 SNPs exert their effects on BMD risk indirectly through little‐studied long noncoding RNA (lncRNA) genes, which may, in turn, control the nearby bone‐related protein‐encoding gene. Our study illustrates a method to identify novel BMD‐related causal regulatory SNPs for future study and to prioritize candidate regulatory GWAS‐derived SNPs, in general. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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spelling pubmed-81016242021-05-10 Prioritization of Osteoporosis‐Associated Genome‐wide Association Study (GWAS) Single‐Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics Zhang, Xiao Deng, Hong‐Wen Shen, Hui Ehrlich, Melanie JBMR Plus Original Articles Genetic risk factors for osteoporosis, a prevalent disease associated with aging, have been examined in many genome‐wide association studies (GWASs). A major challenge is to prioritize transcription‐regulatory GWAS‐derived variants that are likely to be functional. Given the critical role of epigenetics in gene regulation, we have used an unusual epigenetics‐based and transcription‐based approach to identify some of the credible regulatory single‐nucleotide polymorphisms (SNPs) relevant to osteoporosis from 38 reported bone mineral density (BMD) GWASs. Using Roadmap databases, we prioritized SNPs based upon their overlap with strong enhancer or promoter chromatin preferentially in osteoblasts relative to 12 heterologous cell culture types. We also required that these SNPs overlap open chromatin (Deoxyribonuclease I [DNaseI]‐hypersensitive sites) and DNA sequences predicted to bind to osteoblast‐relevant transcription factors in an allele‐specific manner. From >50,000 GWAS‐derived SNPs, we identified 14 novel and credible regulatory SNPs (Tier‐1 SNPs) for osteoporosis risk. Their associated genes, BICC1, LGR4, DAAM2, NPR3, or HMGA2, are involved in osteoblastogenesis or bone homeostasis and regulate cell signaling or enhancer function. Four of these genes are preferentially expressed in osteoblasts. BICC1, LGR4, and DAAM2 play important roles in canonical Wnt signaling, a pathway critical for bone formation and repair. The transcription factors predicted to bind to the Tier‐1 SNP‐containing DNA sequences also have bone‐related functions. We present evidence that some of the Tier‐1 SNPs exert their effects on BMD risk indirectly through little‐studied long noncoding RNA (lncRNA) genes, which may, in turn, control the nearby bone‐related protein‐encoding gene. Our study illustrates a method to identify novel BMD‐related causal regulatory SNPs for future study and to prioritize candidate regulatory GWAS‐derived SNPs, in general. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. John Wiley & Sons, Inc. 2021-03-19 /pmc/articles/PMC8101624/ /pubmed/33977200 http://dx.doi.org/10.1002/jbm4.10481 Text en © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Zhang, Xiao
Deng, Hong‐Wen
Shen, Hui
Ehrlich, Melanie
Prioritization of Osteoporosis‐Associated Genome‐wide Association Study (GWAS) Single‐Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics
title Prioritization of Osteoporosis‐Associated Genome‐wide Association Study (GWAS) Single‐Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics
title_full Prioritization of Osteoporosis‐Associated Genome‐wide Association Study (GWAS) Single‐Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics
title_fullStr Prioritization of Osteoporosis‐Associated Genome‐wide Association Study (GWAS) Single‐Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics
title_full_unstemmed Prioritization of Osteoporosis‐Associated Genome‐wide Association Study (GWAS) Single‐Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics
title_short Prioritization of Osteoporosis‐Associated Genome‐wide Association Study (GWAS) Single‐Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics
title_sort prioritization of osteoporosis‐associated genome‐wide association study (gwas) single‐nucleotide polymorphisms (snps) using epigenomics and transcriptomics
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101624/
https://www.ncbi.nlm.nih.gov/pubmed/33977200
http://dx.doi.org/10.1002/jbm4.10481
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