Multitissue H3K27ac Profiling of GTEx Samples Links Epigenomic Variation to Disease

Overview

Journal Nat Genet

Specialty Genetics

Date 2023 Sep 28

PMID 37770633

Authors

Lei Hou

Xushen Xiong

Yongjin Park

Carles Boix

Benjamin James

Na Sun

Liang He

Aman Patel

Zhizhuo Zhang

Benoit Molinie

Nicholas Van Wittenberghe

Scott Steelman

Chad Nusbaum

Francois Aguet

Kristin G Ardlie

Manolis Kellis

Affiliations

Soon will be listed here.

Abstract

Genetic variants associated with complex traits are primarily noncoding, and their effects on gene-regulatory activity remain largely uncharacterized. To address this, we profile epigenomic variation of histone mark H3K27ac across 387 brain, heart, muscle and lung samples from Genotype-Tissue Expression (GTEx). We annotate 282 k active regulatory elements (AREs) with tissue-specific activity patterns. We identify 2,436 sex-biased AREs and 5,397 genetically influenced AREs associated with 130 k genetic variants (haQTLs) across tissues. We integrate genetic and epigenomic variation to provide mechanistic insights for disease-associated loci from 55 genome-wide association studies (GWAS), by revealing candidate tissues of action, driver SNPs and impacted AREs. Lastly, we build ARE-gene linking scores based on genetics (gLink scores) and demonstrate their unique ability to prioritize SNP-ARE-gene circuits. Overall, our epigenomic datasets, computational integration and mechanistic predictions provide valuable resources and important insights for understanding the molecular basis of human diseases/traits such as schizophrenia.

Citing Articles

Atlas of imprinted and allele-specific DNA methylation in the human body.

Rosenski J, Peretz A, Magenheim J, Loyfer N, Shemer R, Glaser B Nat Commun. 2025; 16(1):2141.

PMID: 40069157 PMC: 11897249. DOI: 10.1038/s41467-025-57433-1.

Transplantation of engineered endothelial progenitor cells with H19 overexpression promotes arterial reendothelialization and inhibits neointimal hyperplasia.

Ye Y, Huang L, Wang K, Sun Y, Zhou Z, Deng T J Tissue Eng. 2025; 16:20417314251315959.

PMID: 39974657 PMC: 11837068. DOI: 10.1177/20417314251315959.

dHICA: a deep transformer-based model enables accurate histone imputation from chromatin accessibility.

Wen W, Zhong J, Zhang Z, Jia L, Chu T, Wang N Brief Bioinform. 2024; 25(6).

PMID: 39316943 PMC: 11421843. DOI: 10.1093/bib/bbae459.

Phosphatase LHPP confers prostate cancer ferroptosis activation by modulating the AKT-SKP2-ACSL4 pathway.

Xie G, Li N, Li K, Xu Y, Zhang Y, Cao S Cell Death Dis. 2024; 15(9):665.

PMID: 39261475 PMC: 11390745. DOI: 10.1038/s41419-024-07007-8.

Crosstalk between epitranscriptomic and epigenomic modifications and its implication in human diseases.

Li C, Chen K, Fang Q, Shi S, Nan J, He J Cell Genom. 2024; 4(8):100605.

PMID: 38981476 PMC: 11406187. DOI: 10.1016/j.xgen.2024.100605.

References

Buniello A, MacArthur J, Cerezo M, Harris L, Hayhurst J, Malangone C . The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2018; 47(D1):D1005-D1012. PMC: 6323933. DOI: 10.1093/nar/gky1120. View

Ward L, Kellis M . Interpreting noncoding genetic variation in complex traits and human disease. Nat Biotechnol. 2012; 30(11):1095-106. PMC: 3703467. DOI: 10.1038/nbt.2422. View

Maurano M, Humbert R, Rynes E, Thurman R, Haugen E, Wang H . Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012; 337(6099):1190-5. PMC: 3771521. DOI: 10.1126/science.1222794. View

Claussnitzer M, Cho J, Collins R, Cox N, Dermitzakis E, Hurles M . A brief history of human disease genetics. Nature. 2020; 577(7789):179-189. PMC: 7405896. DOI: 10.1038/s41586-019-1879-7. View

Trynka G, Sandor C, Han B, Xu H, Stranger B, Liu X . Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat Genet. 2012; 45(2):124-30. PMC: 3826950. DOI: 10.1038/ng.2504. View

Pickrell J . Joint analysis of functional genomic data and genome-wide association studies of 18 human traits. Am J Hum Genet. 2014; 94(4):559-73. PMC: 3980523. DOI: 10.1016/j.ajhg.2014.03.004. View

Gusev A, Lee S, Trynka G, Finucane H, Vilhjalmsson B, Xu H . Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am J Hum Genet. 2014; 95(5):535-52. PMC: 4225595. DOI: 10.1016/j.ajhg.2014.10.004. View

Finucane H, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh P . Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet. 2015; 47(11):1228-35. PMC: 4626285. DOI: 10.1038/ng.3404. View

Ward L, Kellis M . HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2011; 40(Database issue):D930-4. PMC: 3245002. DOI: 10.1093/nar/gkr917. View

10.

Ritchie G, Dunham I, Zeggini E, Flicek P . Functional annotation of noncoding sequence variants. Nat Methods. 2014; 11(3):294-6. PMC: 5015703. DOI: 10.1038/nmeth.2832. View

11.

Lee D, Gorkin D, Baker M, Strober B, Asoni A, McCallion A . A method to predict the impact of regulatory variants from DNA sequence. Nat Genet. 2015; 47(8):955-61. PMC: 4520745. DOI: 10.1038/ng.3331. View

12.

Farh K, Marson A, Zhu J, Kleinewietfeld M, Housley W, Beik S . Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2014; 518(7539):337-43. PMC: 4336207. DOI: 10.1038/nature13835. View

13.

Schaid D, Chen W, Larson N . From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat Rev Genet. 2018; 19(8):491-504. PMC: 6050137. DOI: 10.1038/s41576-018-0016-z. View

14.

Claussnitzer M, Dankel S, Kim K, Quon G, Meuleman W, Haugen C . FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. N Engl J Med. 2015; 373(10):895-907. PMC: 4959911. DOI: 10.1056/NEJMoa1502214. View

15.

Fulco C, Nasser J, Jones T, Munson G, Bergman D, Subramanian V . Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations. Nat Genet. 2019; 51(12):1664-1669. PMC: 6886585. DOI: 10.1038/s41588-019-0538-0. View

16.

Boix C, James B, Park Y, Meuleman W, Kellis M . Regulatory genomic circuitry of human disease loci by integrative epigenomics. Nature. 2021; 590(7845):300-307. PMC: 7875769. DOI: 10.1038/s41586-020-03145-z. View

17.

Lappalainen T, Sammeth M, Friedlander M, t Hoen P, Monlong J, Rivas M . Transcriptome and genome sequencing uncovers functional variation in humans. Nature. 2013; 501(7468):506-11. PMC: 3918453. DOI: 10.1038/nature12531. View

18.

Lloyd-Jones L, Holloway A, McRae A, Yang J, Small K, Zhao J . The Genetic Architecture of Gene Expression in Peripheral Blood. Am J Hum Genet. 2017; 100(2):371. PMC: 5802995. DOI: 10.1016/j.ajhg.2017.01.026. View

19.

Jiang L, Wang M, Lin S, Jian R, Li X, Chan J . A Quantitative Proteome Map of the Human Body. Cell. 2020; 183(1):269-283.e19. PMC: 7575058. DOI: 10.1016/j.cell.2020.08.036. View

20.

Demanelis K, Jasmine F, Chen L, Chernoff M, Tong L, Delgado D . Determinants of telomere length across human tissues. Science. 2020; 369(6509). PMC: 8108546. DOI: 10.1126/science.aaz6876. View