Interactions between genetic variation and cellular environment in skeletal muscle gene expression

Affiliations


Abstract

From whole organisms to individual cells, responses to environmental conditions are influenced by genetic makeup, where the effect of genetic variation on a trait depends on the environmental context. RNA-sequencing quantifies gene expression as a molecular trait, and is capable of capturing both genetic and environmental effects. In this study, we explore opportunities of using allele-specific expression (ASE) to discover cis-acting genotype-environment interactions (GxE)-genetic effects on gene expression that depend on an environmental condition. Treating 17 common, clinical traits as approximations of the cellular environment of 267 skeletal muscle biopsies, we identify 10 candidate environmental response expression quantitative trait loci (reQTLs) across 6 traits (12 unique gene-environment trait pairs; 10% FDR per trait) including sex, systolic blood pressure, and low-density lipoprotein cholesterol. Although using ASE is in principle a promising approach to detect GxE effects, replication of such signals can be challenging as validation requires harmonization of environmental traits across cohorts and a sufficient sampling of heterozygotes for a transcribed SNP. Comprehensive discovery and replication will require large human transcriptome datasets, or the integration of multiple transcribed SNPs, coupled with standardized clinical phenotyping.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


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KMEL References


References

  1.  
    1. ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57–74. doi: 10.1038/nature11247 - DOI - PMC - PubMed
  2.  
    1. Lemon B, Tjian R (2000) Orchestrated response: a symphony of transcription factors for gene control. Genes Dev 14: 2551–2569. doi: 10.1101/gad.831000 - DOI - PubMed
  3.  
    1. Nica AC, Dermitzakis ET (2013) Expression quantitative trait loci: present and future. Philos Trans R Soc Lond B Biol Sci 368: 20120362 doi: 10.1098/rstb.2012.0362 - DOI - PMC - PubMed
  4.  
    1. Albert FW, Kruglyak L (2015) The role of regulatory variation in complex traits and disease. Nat Rev Genet 16: 197–212. doi: 10.1038/nrg3891 - DOI - PubMed
  5.  
    1. Hunter DJ (2005) Gene-environment interactions in human diseases. Nat Rev Genet 6: 287–298. doi: 10.1038/nrg1578 - DOI - PubMed
  6.  
    1. Smirnov DA, Morley M, Shin E, Spielman RS, Cheung VG (2009) Genetic analysis of radiation-induced changes in human gene expression. Nature 459: 587–591. doi: 10.1038/nature07940 - DOI - PMC - PubMed
  7.  
    1. Buil A, Brown AA, Lappalainen T, Viñuela A, Davies MN, et al. (2015) Gene-gene and gene-environment interactions detected by transcriptome sequence analysis in twins. Nat Genet 47: 88–91. doi: 10.1038/ng.3162 - DOI - PMC - PubMed
  8.  
    1. Barreiro LB, Tailleux L, Pai AA, Gicquel B, Marioni JC, et al. (2012) Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection. Proc Natl Acad Sci USA 109: 1204–1209. doi: 10.1073/pnas.1115761109 - DOI - PMC - PubMed
  9.  
    1. Maranville JC, Luca F, Stephens M, Di Rienzo A (2012) Mapping gene-environment interactions at regulatory polymorphisms: insights into mechanisms of phenotypic variation. Transcription 3: 56–62. doi: 10.4161/trns.19497 - DOI - PubMed
  10.  
    1. Moyerbrailean GA, Richards AL, Kurtz D, Kalita CA, Davis GO, et al. (2016) High-throughput allele-specific expression across 250 environmental conditions. Genome Res 26: 1627–1638. doi: 10.1101/gr.209759.116 - DOI - PMC - PubMed
  11.  
    1. Romanoski CE, Lee S, Kim MJ, Ingram-Drake L, Plaisier CL, et al. (2010) Systems genetics analysis of gene-by-environment interactions in human cells. Am J Hum Genet 86: 399–410. doi: 10.1016/j.ajhg.2010.02.002 - DOI - PMC - PubMed
  12.  
    1. Fairfax BP, Humburg P, Makino S, Naranbhai V, Wong D, et al. (2014) Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science (80-) 343: 1246949 doi: 10.1126/science.1246949 - DOI - PMC - PubMed
  13.  
    1. Idaghdour Y, Quinlan J, Goulet J-P, Berghout J, Gbeha E, et al. (2012) Evidence for additive and interaction effects of host genotype and infection in malaria. Proc Natl Acad Sci USA 109: 16786–16793. doi: 10.1073/pnas.1204945109 - DOI - PMC - PubMed
  14.  
    1. Mangravite LM, Engelhardt BE, Medina MW, Smith JD, Brown CD, et al. (2013) A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Nature 502: 377–380. doi: 10.1038/nature12508 - DOI - PMC - PubMed
  15.  
    1. Grundberg E, Adoue V, Kwan T, Ge B, Duan QL, et al. (2011) Global analysis of the impact of environmental perturbation on cis-regulation of gene expression. PLoS Genet 7: e1001279 doi: 10.1371/journal.pgen.1001279 - DOI - PMC - PubMed
  16.  
    1. Raj T, Rothamel K, Mostafavi S, Ye C, Lee MN, et al. (2014) Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science (80-) 344: 519–523. doi: 10.1126/science.1249547 - DOI - PMC - PubMed
  17.  
    1. Ye CJ, Feng T, Kwon H-K, Raj T, Wilson MT, et al. (2014) Intersection of population variation and autoimmunity genetics in human T cell activation. Science (80-) 345: 1254665 doi: 10.1126/science.1254665 - DOI - PMC - PubMed
  18.  
    1. Lee MN, Ye C, Villani A-C, Raj T, Li W, et al. (2014) Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science (80-) 343: 1246980 doi: 10.1126/science.1246980 - DOI - PMC - PubMed
  19.  
    1. Zhernakova DV, Deelen P, Vermaat M, van Iterson M, van Galen M, et al. (2017) Identification of context-dependent expression quantitative trait loci in whole blood. Nat Genet 49: 139–145. doi: 10.1038/ng.3737 - DOI - PubMed
  20.  
    1. Knowles DA, Davis JR, Edgington H, Raj A, Favé M-J, et al. (2017) Allele-specific expression reveals interactions between genetic variation and environment. Nat Methods 14: 699–702. doi: 10.1038/nmeth.4298 - DOI - PMC - PubMed
  21.  
    1. Gagneur J, Stegle O, Zhu C, Jakob P, Tekkedil MM, et al. (2013) Genotype-environment interactions reveal causal pathways that mediate genetic effects on phenotype. PLoS Genet 9: e1003803 doi: 10.1371/journal.pgen.1003803 - DOI - PMC - PubMed
  22.  
    1. Landry CR, Oh J, Hartl DL, Cavalieri D (2006) Genome-wide scan reveals that genetic variation for transcriptional plasticity in yeast is biased towards multi-copy and dispensable genes. Gene 366: 343–351. doi: 10.1016/j.gene.2005.10.042 - DOI - PubMed
  23.  
    1. Sambandan D, Carbone MA, Anholt RRH, Mackay TFC (2008) Phenotypic plasticity and genotype by environment interaction for olfactory behavior in Drosophila melanogaster. Genetics 179: 1079–1088. doi: 10.1534/genetics.108.086769 - DOI - PMC - PubMed
  24.  
    1. Runcie DE, Garfield DA, Babbitt CC, Wygoda JA, Mukherjee S, et al. (2012) Genetics of gene expression responses to temperature stress in a sea urchin gene network. Mol Ecol 21: 4547–4562. doi: 10.1111/j.1365-294X.2012.05717.x - DOI - PMC - PubMed
  25.  
    1. Smith EN, Kruglyak L (2008) Gene-environment interaction in yeast gene expression. PLoS Biol 6: e83 doi: 10.1371/journal.pbio.0060083 - DOI - PMC - PubMed
  26.  
    1. Li Y, Alvarez OA, Gutteling EW, Tijsterman M, Fu J, et al. (2006) Mapping determinants of gene expression plasticity by genetical genomics in C. elegans. PLoS Genet 2: e222 doi: 10.1371/journal.pgen.0020222 - DOI - PMC - PubMed
  27.  
    1. Castel SE, Levy-Moonshine A, Mohammadi P, Banks E, Lappalainen T (2015) Tools and best practices for data processing in allelic expression analysis. Genome Biol 16: 195 doi: 10.1186/s13059-015-0762-6 - DOI - PMC - PubMed
  28.  
    1. Scott LJ, Erdos MR, Huyghe JR, Welch RP, Beck AT, et al. (2016) The genetic regulatory signature of type 2 diabetes in human skeletal muscle. Nat Commun 7: 11764 doi: 10.1038/ncomms11764 - DOI - PMC - PubMed
  29.  
    1. Keen JC, Moore HM (2015) The Genotype-Tissue Expression (GTEx) Project: Linking Clinical Data with Molecular Analysis to Advance Personalized Medicine. J Pers Med 5: 22–29. doi: 10.3390/jpm5010022 - DOI - PMC - PubMed
  30.  
    1. GTEx Consortium (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45: 580–585. doi: 10.1038/ng.2653 - DOI - PMC - PubMed
  31.  
    1. Paul AS, Pollard TD (2009) Review of the mechanism of processive actin filament elongation by formins. Cell Motil Cytoskeleton 66: 606–617. doi: 10.1002/cm.20379 - DOI - PMC - PubMed
  32.  
    1. Goode BL, Eck MJ (2007) Mechanism and function of formins in the control of actin assembly. Annu Rev Biochem 76: 593–627. doi: 10.1146/annurev.biochem.75.103004.142647 - DOI - PubMed
  33.  
    1. Campellone KG, Welch MD (2010) A nucleator arms race: cellular control of actin assembly. Nat Rev Mol Cell Biol 11: 237–251. doi: 10.1038/nrm2867 - DOI - PMC - PubMed
  34.  
    1. Rosado M, Barber CF, Berciu C, Feldman S, Birren SJ, et al. (2014) Critical roles for multiple formins during cardiac myofibril development and repair. Mol Biol Cell 25: 811–827. doi: 10.1091/mbc.E13-08-0443 - DOI - PMC - PubMed
  35.  
    1. Kan-O M, Takeya R, Abe T, Kitajima N, Nishida M, et al. (2012) Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis. Biol Open 1: 889–896. doi: 10.1242/bio.20121370 - DOI - PMC - PubMed
  36.  
    1. Wooten EC, Hebl VB, Wolf MJ, Greytak SR, Orr NM, et al. (2013) Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy. Circ Cardiovasc Genet 6: 10–18. doi: 10.1161/CIRCGENETICS.112.965277 - DOI - PMC - PubMed
  37.  
    1. Iskratsch T, Lange S, Dwyer J, Kho AL, dos Remedios C, et al. (2010) Formin follows function: a muscle-specific isoform of FHOD3 is regulated by CK2 phosphorylation and promotes myofibril maintenance. J Cell Biol 191: 1159–1172. doi: 10.1083/jcb.201005060 - DOI - PMC - PubMed
  38.  
    1. Kanaya H, Takeya R, Takeuchi K, Watanabe N, Jing N, et al. (2005) Fhos2, a novel formin-related actin-organizing protein, probably associates with the nestin intermediate filament. Genes Cells 10: 665–678. doi: 10.1111/j.1365-2443.2005.00867.x - DOI - PubMed
  39.  
    1. Iskratsch T, Reijntjes S, Dwyer J, Toselli P, Dégano IR, et al. (2013) Two distinct phosphorylation events govern the function of muscle FHOD3. Cell Mol Life Sci 70: 893–908. doi: 10.1007/s00018-012-1154-7 - DOI - PMC - PubMed
  40.  
    1. Parker SCJ, Stitzel ML, Taylor DL, Orozco JM, Erdos MR, et al. (2013) Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc Natl Acad Sci USA 110: 17921–17926. doi: 10.1073/pnas.1317023110 - DOI - PMC - PubMed
  41.  
    1. Fuchsberger C, Abecasis GR, Hinds DA (2015) minimac2: faster genotype imputation. Bioinformatics 31: 782–784. doi: 10.1093/bioinformatics/btu704 - DOI - PMC - PubMed
  42.  
    1. Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18: 499–502. - PubMed
  43.  
    1. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, et al. (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25: 2078–2079. doi: 10.1093/bioinformatics/btp352 - DOI - PMC - PubMed
  44.  
    1. Lappalainen T, Sammeth M, Friedländer MR, ‘t Hoen PAC, Monlong J, et al. (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501: 506–511. doi: 10.1038/nature12531 - DOI - PMC - PubMed
  45.  
    1. Stegle O, Parts L, Durbin R, Winn J (2010) A Bayesian framework to account for complex non-genetic factors in gene expression levels greatly increases power in eQTL studies. PLoS Comput Biol 6: e1000770 doi: 10.1371/journal.pcbi.1000770 - DOI - PMC - PubMed
  46.  
    1. Stegle O, Parts L, Piipari M, Winn J, Durbin R (2012) Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analyses. Nat Protoc 7: 500–507. doi: 10.1038/nprot.2011.457 - DOI - PMC - PubMed
  47.  
    1. Li S, Łabaj PP, Zumbo P, Sykacek P, Shi W, et al. (2014) Detecting and correcting systematic variation in large-scale RNA sequencing data. Nat Biotechnol 32: 888–895. doi: 10.1038/nbt.3000 - DOI - PMC - PubMed
  48.  
    1. Lippert C, Casale FP, Rakitsch B, Stegle O (2014) LIMIX: genetic analysis of multiple traits. BioRxiv. doi: 10.1101/003905 - DOI
  49.  
    1. Casale FP, Rakitsch B, Lippert C, Stegle O (2015) Efficient set tests for the genetic analysis of correlated traits. Nat Methods 12: 755–758. doi: 10.1038/nmeth.3439 - DOI - PubMed
  50.  
    1. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B (Methodological) 57: 289–300.
  51.  
    1. GTEx Consortium (2015) Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science (80-) 348: 648–660. doi: 10.1126/science.1262110 - DOI - PMC - PubMed
  52.  
    1. Varshney A, Scott LJ, Welch RP, Erdos MR, Chines PS, et al. (2017) Genetic regulatory signatures underlying islet gene expression and type 2 diabetes. Proc Natl Acad Sci USA 114: 2301–2306. doi: 10.1073/pnas.1621192114 - DOI - PMC - PubMed
  53.  
    1. Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, et al. (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473: 43–49. doi: 10.1038/nature09906 - DOI - PMC - PubMed
  54.  
    1. Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, et al. (2015) Integrative analysis of 111 reference human epigenomes. Nature 518: 317–330. doi: 10.1038/nature14248 - DOI - PMC - PubMed
  55.  
    1. Mikkelsen TS, Xu Z, Zhang X, Wang L, Gimble JM, et al. (2010) Comparative epigenomic analysis of murine and human adipogenesis. Cell 143: 156–169. doi: 10.1016/j.cell.2010.09.006 - DOI - PMC - PubMed
  56.  
    1. Ernst J, Kellis M (2012) ChromHMM: automating chromatin-state discovery and characterization. Nat Methods 9: 215–216. doi: 10.1038/nmeth.1906 - DOI - PMC - PubMed
  57.  
    1. Ernst J, Kellis M (2010) Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat Biotechnol 28: 817–825. doi: 10.1038/nbt.1662 - DOI - PMC - PubMed
  58.  
    1. Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ (2013) Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods 10: 1213–1218. doi: 10.1038/nmeth.2688 - DOI - PMC - PubMed
  59.  
    1. Allum F, Shao X, Guénard F, Simon M-M, Busche S, et al. (2015) Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants. Nat Commun 6: 7211 doi: 10.1038/ncomms8211 - DOI - PMC - PubMed
  60.  
    1. Mathelier A, Fornes O, Arenillas DJ, Chen C-Y, Denay G, et al. (2016) JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles. Nucleic Acids Res 44: D110–5. doi: 10.1093/nar/gkv1176 - DOI - PMC - PubMed
  61.  
    1. Kheradpour P, Kellis M (2014) Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res 42: 2976–2987. doi: 10.1093/nar/gkt1249 - DOI - PMC - PubMed
  62.  
    1. Jolma A, Yan J, Whitington T, Toivonen J, Nitta KR, et al. (2013) DNA-binding specificities of human transcription factors. Cell 152: 327–339. doi: 10.1016/j.cell.2012.12.009 - DOI - PubMed
  63.  
    1. Grant CE, Bailey TL, Noble WS (2011) FIMO: scanning for occurrences of a given motif. Bioinformatics 27: 1017–1018. doi: 10.1093/bioinformatics/btr064 - DOI - PMC - PubMed
  64.  
    1. Bailey TL, Johnson J, Grant CE, Noble WS (2015) The MEME Suite. Nucleic Acids Res 43: W39–49. doi: 10.1093/nar/gkv416 - DOI - PMC - PubMed