Integrative Tissue-Specific Functional Annotations in the Human Genome Provide Novel Insights on Many Complex Traits and Improve Signal Prioritization in Genome Wide Association Studies

Extensive efforts have been made to understand genomic function through both experimental and computational approaches, yet proper annotation still remains challenging, especially in non-coding regions. In this manuscript, we introduce GenoSkyline, an unsupervised learning framework to predict tissu...

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Main Authors:	Lu, Qiongshi, Powles, Ryan Lee, Wang, Qian, He, Beixin Julie, Zhao, Hongyu
Format:	Online
Language:	English
Published:	Public Library of Science 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825932/

id	pubmed-4825932
recordtype	oai_dc
spelling	pubmed-48259322016-04-22 Integrative Tissue-Specific Functional Annotations in the Human Genome Provide Novel Insights on Many Complex Traits and Improve Signal Prioritization in Genome Wide Association Studies Lu, Qiongshi Powles, Ryan Lee Wang, Qian He, Beixin Julie Zhao, Hongyu Research Article Extensive efforts have been made to understand genomic function through both experimental and computational approaches, yet proper annotation still remains challenging, especially in non-coding regions. In this manuscript, we introduce GenoSkyline, an unsupervised learning framework to predict tissue-specific functional regions through integrating high-throughput epigenetic annotations. GenoSkyline successfully identified a variety of non-coding regulatory machinery including enhancers, regulatory miRNA, and hypomethylated transposable elements in extensive case studies. Integrative analysis of GenoSkyline annotations and results from genome-wide association studies (GWAS) led to novel biological insights on the etiologies of a number of human complex traits. We also explored using tissue-specific functional annotations to prioritize GWAS signals and predict relevant tissue types for each risk locus. Brain and blood-specific annotations led to better prioritization performance for schizophrenia than standard GWAS p-values and non-tissue-specific annotations. As for coronary artery disease, heart-specific functional regions was highly enriched of GWAS signals, but previously identified risk loci were found to be most functional in other tissues, suggesting a substantial proportion of still undetected heart-related loci. In summary, GenoSkyline annotations can guide genetic studies at multiple resolutions and provide valuable insights in understanding complex diseases. GenoSkyline is available at http://genocanyon.med.yale.edu/GenoSkyline. Public Library of Science 2016-04-08 /pmc/articles/PMC4825932/ /pubmed/27058395 http://dx.doi.org/10.1371/journal.pgen.1005947 Text en © 2016 Lu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Lu, Qiongshi Powles, Ryan Lee Wang, Qian He, Beixin Julie Zhao, Hongyu
spellingShingle	Lu, Qiongshi Powles, Ryan Lee Wang, Qian He, Beixin Julie Zhao, Hongyu Integrative Tissue-Specific Functional Annotations in the Human Genome Provide Novel Insights on Many Complex Traits and Improve Signal Prioritization in Genome Wide Association Studies
author_facet	Lu, Qiongshi Powles, Ryan Lee Wang, Qian He, Beixin Julie Zhao, Hongyu
author_sort	Lu, Qiongshi
title	Integrative Tissue-Specific Functional Annotations in the Human Genome Provide Novel Insights on Many Complex Traits and Improve Signal Prioritization in Genome Wide Association Studies
title_short	Integrative Tissue-Specific Functional Annotations in the Human Genome Provide Novel Insights on Many Complex Traits and Improve Signal Prioritization in Genome Wide Association Studies
title_full	Integrative Tissue-Specific Functional Annotations in the Human Genome Provide Novel Insights on Many Complex Traits and Improve Signal Prioritization in Genome Wide Association Studies
title_fullStr	Integrative Tissue-Specific Functional Annotations in the Human Genome Provide Novel Insights on Many Complex Traits and Improve Signal Prioritization in Genome Wide Association Studies
title_full_unstemmed	Integrative Tissue-Specific Functional Annotations in the Human Genome Provide Novel Insights on Many Complex Traits and Improve Signal Prioritization in Genome Wide Association Studies
title_sort	integrative tissue-specific functional annotations in the human genome provide novel insights on many complex traits and improve signal prioritization in genome wide association studies
description	Extensive efforts have been made to understand genomic function through both experimental and computational approaches, yet proper annotation still remains challenging, especially in non-coding regions. In this manuscript, we introduce GenoSkyline, an unsupervised learning framework to predict tissue-specific functional regions through integrating high-throughput epigenetic annotations. GenoSkyline successfully identified a variety of non-coding regulatory machinery including enhancers, regulatory miRNA, and hypomethylated transposable elements in extensive case studies. Integrative analysis of GenoSkyline annotations and results from genome-wide association studies (GWAS) led to novel biological insights on the etiologies of a number of human complex traits. We also explored using tissue-specific functional annotations to prioritize GWAS signals and predict relevant tissue types for each risk locus. Brain and blood-specific annotations led to better prioritization performance for schizophrenia than standard GWAS p-values and non-tissue-specific annotations. As for coronary artery disease, heart-specific functional regions was highly enriched of GWAS signals, but previously identified risk loci were found to be most functional in other tissues, suggesting a substantial proportion of still undetected heart-related loci. In summary, GenoSkyline annotations can guide genetic studies at multiple resolutions and provide valuable insights in understanding complex diseases. GenoSkyline is available at http://genocanyon.med.yale.edu/GenoSkyline.
publisher	Public Library of Science
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825932/
_version_	1613564182809018368

Integrative Tissue-Specific Functional Annotations in the Human Genome Provide Novel Insights on Many Complex Traits and Improve Signal Prioritization in Genome Wide Association Studies

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