Genome-wide association study identifies 16 genomic regions associated with circulating cytokines at birth

Autoři: Yunpeng Wang aff001;  Ron Nudel aff001;  Michael E. Benros aff001;  Kristin Skogstrand aff001;  Simon Fishilevich aff008;  ;  Doron Lancet aff008;  Jiangming Sun aff001;  David M. Hougaard aff001;  Ole A. Andreassen aff003;  Preben Bo Mortensen aff001;  Alfonso Buil aff001;  Thomas F. Hansen aff001;  Wesley K. Thompson aff001;  Thomas Werge aff001
Působiště autorů: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark aff001;  Institute of Biological Psychiatry, Mental Health Center St. Hans, Mental Health Services Copenhagen, Denmark aff002;  Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, and Oslo University Hospital, Norway aff003;  Lifespan Changes in Brain and Cognition (LCBC), Department of Psychology, University of Oslo, Norway aff004;  Mental Health Center Copenhagen, Copenhagen University Hospital, Denmark aff005;  Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark aff006;  Danish Centre for Neonatal Screening, Department of Congenital Diseases, Statens Serum Institut, Denmark aff007;  Department of Molecular Genetics, Weizmann Institute of Science, Israel aff008;  Department of Economics and Business Economics-National Centre for Register-based Research, University of Aarhus, Denmark aff009;  Danish Headache Center, Department of Neurology, University Hospital Copenhagen, Denmark aff010;  Division of Biostatistics, Department of Family Medicine and Public Health, University of California, San Diego, California, United States of America aff011;  Department of Clinical Medicine, University of Copenhagen, Denmark aff012
Vyšlo v časopise: Genome-wide association study identifies 16 genomic regions associated with circulating cytokines at birth. PLoS Genet 16(11): e1009163. doi:10.1371/journal.pgen.1009163
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009163


Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10−9), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.

Klíčová slova:

Cytokines – Gene regulation – Genetics of disease – Genome annotation – Genomics – Inflammation – Inflammatory diseases – Single nucleotide polymorphisms


1. Lackie J. Dictionary of Biomedicine—Oxford Reference. 1 ed. Oxford, UK: Oxford University Press; 2010.

2. Zhang J-M, An J. Cytokines, Inflammation, and Pain. Int Anesthesiol Clin. 2007;45(2):27–37. doi: 10.1097/AIA.0b013e318034194e 17426506

3. Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer. 2004;4(1):11–22. doi: 10.1038/nrc1252 14708024

4. Braunwald E. Biomarkers in heart failure. N Engl J Med. 2008;358(20):2148–59. doi: 10.1056/NEJMra0800239 18480207

5. Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542:177–85. doi: 10.1038/nature21363 28179656

6. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14(5):329–42. doi: 10.1038/nri3661 24751956

7. Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O. Neuroinflammation and psychiatric illness. J Neuroinflammation. 2013;10:43. doi: 10.1186/1742-2094-10-43 23547920

8. Kim S, Keku TO, Martin C, Galanko J, Woosley JT, Schroeder JC, et al. Circulating Levels of Inflammatory Cytokines and Risk of Colorectal Adenomas. Cancer Res. 2008;68(1):323–8. doi: 10.1158/0008-5472.CAN-07-2924 18172326

9. da Cruz Fernandes IM, Pinto RZ, Ferreira P, Lira FS. Low back pain, obesity, and inflammatory markers: exercise as potential treatment. J Exerc Rehabil. 2018;14(2):168–74. doi: 10.12965/jer.1836070.035 29740548

10. Pollmächer T, Haack M, Schuld A, Reichenberg A, Yirmiya R. Low levels of circulating inflammatory cytokines—Do they affect human brain functions? Brain Behav Immun. 2002;16(5):525–32. doi: 10.1016/s0889-1591(02)00004-1 12401466

11. Nudel R, Benros ME, Krebs MD, Allesøe RL, Lemvigh CK, Bybjerg-Grauholm J, et al. Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders. Eur J Hum Genet. 2019;27(9):1445–55. doi: 10.1038/s41431-019-0402-9 30976114

12. Nudel R, Wang Y, Appadurai V, Schork AJ, Buil A, Agerbo E, et al. A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population. Transl Psychiatry. 2019;9(1):283. doi: 10.1038/s41398-019-0622-3 31712607

13. Liu X, Nudel R, Thompson WK, Appadurai V, Schork AJ, Buil A, et al. Genetic factors underlying the bidirectional relationship between autoimmune and mental disorders–findings from a Danish population-based study. Brain Behav Immun. 2020. doi: 10.1016/j.bbi.2020.06.014 32534018

14. Dehghan A, Dupuis J, Barbalic M, Bis JC, Eiriksdottir G, Lu C, et al. Meta-analysis of genome-wide association studies in> 80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation. 2011;123(7):731–8. doi: 10.1161/CIRCULATIONAHA.110.948570 21300955

15. Kettunen J, Tukiainen T, Sarin AP, Ortega-Alonso A, Tikkanen E, Lyytikainen LP, et al. Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nat Genet. 2012;44(3):269–76. doi: 10.1038/ng.1073 22286219

16. Suhre K, Arnold M, Bhagwat AM, Cotton RJ, Engelke R, Raffler J, et al. Connecting genetic risk to disease end points through the human blood plasma proteome. Nat Commun. 2017;8:14357. doi: 10.1038/ncomms14357 28240269

17. Ahola-Olli AV, Wurtz P, Havulinna AS, Aalto K, Pitkanen N, Lehtimaki T, et al. Genome-wide Association Study Identifies 27 Loci Influencing Concentrations of Circulating Cytokines and Growth Factors. Am J Hum Genet. 2017;100(1):40–50. doi: 10.1016/j.ajhg.2016.11.007 27989323

18. Pedersen CB, Bybjerg-Grauholm J, Pedersen MG, Grove J, Agerbo E, Baekvad-Hansen M, et al. The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders. Mol Psychiatry. 2018;23(1):6–14. doi: 10.1038/mp.2017.196 28924187

19. Loh PR, Tucker G, Bulik-Sullivan BK, Vilhjalmsson BJ, Finucane HK, Salem RM, et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015;47(3):284–90. doi: 10.1038/ng.3190 25642633

20. Choi SH, Ruggiero D, Sorice R, Song C, Nutile T, Vernon Smith A, et al. Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies. PLoS Genet. 2016;12(2):e1005874. doi: 10.1371/journal.pgen.1005874 26910538

21. Shin SY, Fauman EB, Petersen AK, Krumsiek J, Santos R, Huang J, et al. An atlas of genetic influences on human blood metabolites. Nat Genet. 2014;46(6):543–50. doi: 10.1038/ng.2982 24816252

22. Astle WJ, Elding H, Jiang T, Allen D, Ruklisa D, Mann AL, et al. The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease. Cell. 2016;167(5):1415–29 e19. doi: 10.1016/j.cell.2016.10.042 27863252

23. Goldstein JI, Jarskog LF, Hilliard C, Alfirevic A, Duncan L, Fourches D, et al. Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. Nat Commun. 2014;5:4757. doi: 10.1038/ncomms5757 25187353

24. Benner C, Spencer CC, Havulinna AS, Salomaa V, Ripatti S, Pirinen M. FINEMAP: efficient variable selection using summary data from genome-wide association studies. Bioinformatics. 2016;32(10):1493–501. doi: 10.1093/bioinformatics/btw018 26773131

25. Fishilevich S, Nudel R, Rappaport N, Hadar R, Plaschkes I, Iny Stein T, et al. GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database: the journal of biological databases and curation. 2017;2017:bax028. doi: 10.1093/database/bax028 28605766

26. Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539):317–30. doi: 10.1038/nature14248 25693563

27. Consortium GTEx. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348(6235):648–60. doi: 10.1126/science.1262110 25954001

28. Kavanagh D, Dwyer S, O'Donovan M, Owen M. The ENCODE project: implications for psychiatric genetics. Mol Psychiatry. 2013;18(5):540–2. doi: 10.1038/mp.2013.13 23478746

29. Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, et al. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Curr Protoc Bioinformatics. 2016;54:1.30.1–1..3. doi: 10.1002/cpbi.5 27322403

30. Gelernter J. Genetics of Complex Traits in Psychiatry. Biol Psychiatry. 2015;77(1):36–42. doi: 10.1016/j.biopsych.2014.08.005 25444161

31. Rosenblum MD, Remedios KA, Abbas AK. Mechanisms of human autoimmunity. J Clin Invest. 2015;125(6):2228–33. doi: 10.1172/JCI78088 25893595

32. Simmonds MJ, Gough SCL. Genetic insights into disease mechanisms of autoimmunity. Br Med Bull. 2005;71(1):93–113. doi: 10.1093/bmb/ldh032 15701924

33. Schizophrenia Working Group of the Psychiatric Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;(511):421–7. doi: 10.1038/nature13595 25056061

34. Bearden CE, Freimer NB. Endophenotypes for psychiatric disorders: ready for primetime? Trends Genet. 2006;22(6):306–13. doi: 10.1016/j.tig.2006.04.004 16697071

35. Iacono WG. Endophenotypes in psychiatric disease: prospects and challenges. Genome Med. 2018;10(1):11. doi: 10.1186/s13073-018-0526-5 29471866

36. Davey Smith G, Ebrahim S, Lewis S, Hansell AL, Palmer LJ, Burton PR. Genetic epidemiology and public health: hope, hype, and future prospects. Lancet (London, England). 2005;366(9495):1484–98.

37. Skogstrand K. Multiplex assays of inflammatory markers, a description of methods and discussion of precautions—Our experience through the last ten years. Methods (San Diego, Calif). 2012;56(2):204–12. doi: 10.1016/j.ymeth.2011.09.025 22001645

38. Skogstrand K, Thorsen P, Norgaard-Pedersen B, Schendel DE, Sorensen LC, Hougaard DM. Simultaneous measurement of 25 inflammatory markers and neurotrophins in neonatal dried blood spots by immunoassay with xMAP technology. Clin Chem. 2005;51(10):1854–66. doi: 10.1373/clinchem.2005.052241 16081507

39. Skogstrand K, Hagen CM, Borbye-Lorenzen N, Christiansen M, Bybjerg-Grauholm J, Baekvad-Hansen M, et al. Reduced neonatal brain-derived neurotrophic factor is associated with autism spectrum disorders. Transl Psychiatry. 2019;9(1):252. doi: 10.1038/s41398-019-0587-2 31591381

40. Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet. 2012;44(8):955–9. doi: 10.1038/ng.2354 22820512

41. Delaneau O, Marchini J, Zagury J-F. A linear complexity phasing method for thousands of genomes. Nat Methods. 2012;9(2):179–81.

42. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75. doi: 10.1086/519795 17701901

43. Patterson N, Price AL, Reich D. Population structure and eigenanalysis. PLoS Genet. 2006;2(12):e190. doi: 10.1371/journal.pgen.0020190 17194218

44. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26(18):2336–7. doi: 10.1093/bioinformatics/btq419 20634204

45. McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, et al. The Ensembl Variant Effect Predictor. Genome Biol. 2016;17(1):122. doi: 10.1186/s13059-016-0974-4 27268795

46. Zerbino DR, Wilder SP, Johnson N, Juettemann T, Flicek PR. The ensembl regulatory build. Genome Biol. 2015;16:56. doi: 10.1186/s13059-015-0621-5 25887522

47. The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74. doi: 10.1038/nature11247 22955616

48. Visel A, Minovitsky S, Dubchak I, Pennacchio LA. VISTA Enhancer Browser—a database of tissue-specific human enhancers. Nucleic Acids Res. 2007;35(Database issue):D88–92. doi: 10.1093/nar/gkl822 17130149

49. Khan A, Zhang X. dbSUPER: a database of super-enhancers in mouse and human genome. Nucleic Acids Res. 2016;44(D1):D164–71. doi: 10.1093/nar/gkv1002 26438538

50. Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, et al. An atlas of active enhancers across human cell types and tissues. Nature. 2014;507(7493):455–61. doi: 10.1038/nature12787 24670763

51. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45(6):580–5. doi: 10.1038/ng.2653 23715323

52. Mifsud B, Tavares-Cadete F, Young AN, Sugar R, Schoenfelder S, Ferreira L, et al. Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat Genet. 2015;47(6):598–606. doi: 10.1038/ng.3286 25938943

Článek vyšel v časopise

PLOS Genetics

2020 Číslo 11

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Zvyšte si kvalifikaci online z pohodlí domova

Snímatelné zubní náhrady a fixační krémy
nový kurz
Autoři: doc. MUDr. Hana Hubálková, Ph.D.

Nová éra v léčbě migrény
Autoři: MUDr. Eva Medová, MUDr. Tomáš Nežádal, Ph.D.

Význam nutraceutik u kardiovaskulárních onemocnění

Pěnová skleroterapie
Autoři: MUDr. Marek Šlais


Všechny kurzy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se