Advertisement

Brain Imaging and Behavior

, Volume 12, Issue 1, pp 13–19 | Cite as

ZNF804A rs1344706 interacts with COMT rs4680 to affect prefrontal volume in healthy adults

  • Qiang Xu
  • Yongqin Xiong
  • Congcong Yuan
  • Feng Liu
  • Fangshi Zhao
  • Junlin Shen
  • Wen Qin
  • Chunshui Yu
Original Research

Abstract

The biological function of ZNF804A rs1344706, the first genome-wide supported risk variant of schizophrenia, remains largely unknown. Based on the upregulating effect of ZNF804A on the expression of COMT, we hypothesize that ZNF804A may affect grey matter volume (GMV) by interacting with COMT. Voxel-based morphometry was applied to analyze the main and interaction effects of ZNF804A rs1344706 and COMT rs4680 on brain GMV in 274 healthy young human subjects. The GMV of the left dorsolateral prefrontal cortex (DLPFC) showed a significant COMT rs4680 × ZNF804A rs1344706 interaction, manifesting as an inverted U-shape modulation by the presumed dopamine signaling. In COMT Met-allele carriers, the ZNF804A TG heterozygotes showed greater GMV in the left DLPFC than both GG and TT homozygotes. In COMT Val/Val homozygotes, however, the ZNF804A TG heterozygotes exhibited smaller GMV in the left DLPFC than GG homozygotes and comparable GMV with TT homozygotes. These findings suggest that ZNF804A affects the GMV of the prefrontal cortex by interacting with COMT, which may improve our understanding of neurobiological effect of ZNF804A and its association with schizophrenia.

Keywords

ZNF804A COMT Single nucleotide polymorphism Grey matter volume Magnetic resonance imaging 

Notes

Compliance with ethical standards

Funding

This study was funded by the Natural Science Foundation of China (Grants number: 81425013, 81271551, 91132301, 81501451 and 81301201).

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11682_2016_9671_MOESM1_ESM.docx (104 kb)
ESM 1 (DOCX 104 kb)

References

  1. Chen, J., Lipska, B. K., Halim, N., Ma, Q. D., Matsumoto, M., Melhem, S., et al. (2004a). Functional analysis of genetic variation in catechol-O-methyltransferase (COMT)_ effects on mRNA, protein, and enzyme activity in postmortem human brain. Human Genetics, 75, 807–821.CrossRefGoogle Scholar
  2. Chen, X., Wang, X., O’Neill, A. F., Walsh, D., & Kendler, K. S. (2004b). Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families. Molecular Psychiatry, 9(10), 962–967. doi: 10.1038/sj.mp.4001519.CrossRefPubMedGoogle Scholar
  3. Ding, H., Qin, W., Jiang, T., Zhang, Y., & Yu, C. (2012). Volumetric variation in subregions of the cerebellum correlates with working memory performance. Neuroscience Letters, 508(1), 47–51. doi: 10.1016/j.neulet.2011.12.016.CrossRefPubMedGoogle Scholar
  4. Esslinger, C., Walter, H., Kirsch, P., Erk, S., Schnell, K., Arnold, C., et al. (2009). Neural mechanisms of a genome-wide supported psychosis variant. Science, 324(5927), 605. doi: 10.1126/science.1167768.CrossRefPubMedGoogle Scholar
  5. Fallon, S. J., Williams-Gray, C. H., Barker, R. A., Owen, A. M., & Hampshire, A. (2013). Prefrontal dopamine levels determine the balance between cognitive stability and flexibility. Cerebral Cortex, 23(2), 361–369. doi: 10.1093/cercor/bhs025.CrossRefPubMedGoogle Scholar
  6. Giakoumaki, S. G., Roussos, P., & Bitsios, P. (2008). Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val158Met polymorphism. Neuropsychopharmacology, 33(13), 3058–3068. doi: 10.1038/npp.2008.82.CrossRefPubMedGoogle Scholar
  7. Girgenti, M. J., LoTurco, J. J., & Maher, B. J. (2012). ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2. PloS One, 7(2), e32404. doi: 10.1371/journal.pone.0032404.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Glahn, D. C., Winkler, A. M., Kochunov, P., Almasy, L., Duggirala, R., Carless, M. A., et al. (2010). Genetic control over the resting brain. Proceedings of the National Academy of Sciences of the United States of America, 107(3), 1223–1228. doi: 10.1073/pnas.0909969107.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Gong, Y. (1982). Manual of modified Wechsler adult intelligence scale (WAIS-RC) (in Chinese). Changsha: Hunan Med College.Google Scholar
  10. Guella, I., & Vawter, M. P. (2014). Allelic imbalance associated with the schizophrenia risk SNP rs1344706 indicates a cis-acting variant in ZNF804A. Schizophrenia Research, 153(1–3), 243–245. doi: 10.1016/j.schres.2014.01.005.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Guella, I., Sequeira, A., Rollins, B., Morgan, L., Myers, R. M., Watson, S. J., et al. (2014). Evidence of allelic imbalance in the schizophrenia susceptibility gene ZNF804A in human dorsolateral prefrontal cortex. Schizophrenia Research, 152(1), 111–116. doi: 10.1016/j.schres.2013.11.021.CrossRefPubMedGoogle Scholar
  12. Hibar, D. P., Stein, J. L., Renteria, M. E., Arias-Vasquez, A., Desrivieres, S., Jahanshad, N., et al. (2015). Common genetic variants influence human subcortical brain structures. Nature, 520(7546), 224–229. doi: 10.1038/nature14101.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Ho, B. C., Andreasen, N. C., Dawson, J. D., & Wassink, T. H. (2007). Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. The American Journal of Psychiatry, 164(12), 1890–1899. doi: 10.1176/appi.ajp.2007.05111903.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Honea, R., Verchinski, B. A., Pezawas, L., Kolachana, B. S., Callicott, J. H., Mattay, V. S., et al. (2009). Impact of interacting functional variants in COMT on regional gray matter volume in human brain. NeuroImage, 45(1), 44–51. doi: 10.1016/j.neuroimage.2008.10.064.CrossRefPubMedGoogle Scholar
  15. Kauppi, K., Westlye, L. T., Tesli, M., Bettella, F., Brandt, C. L., Mattingsdal, M., et al. (2015). Polygenic risk for schizophrenia associated with working memory-related prefrontal brain activation in patients with schizophrenia and healthy controls. Schizophrenia Bulletin, 41(3), 736–743. doi: 10.1093/schbul/sbu152.CrossRefPubMedGoogle Scholar
  16. Kuppers, E., & Beyer, C. (2001). Dopamine regulates brain-derived neurotrophic factor (BDNF) expression in cultured embryonic mouse striatal cells. Neuroreport, 12(6), 1175–1179.CrossRefPubMedGoogle Scholar
  17. Kurth, F., Gaser, C., & Luders, E. (2015). A 12-step user guide for analyzing voxel-wise gray matter asymmetries in statistical parametric mapping (SPM). Nature Protocols, 10(2), 293–304. doi: 10.1038/nprot.2015.014.CrossRefPubMedGoogle Scholar
  18. Lachman, H. M., Papolos, D. F., Saito, T., Yu, Y. M., Szumlanski, C. L., & Weinshilboum, R. M. (1996). Human catechol-O-methyltransferase pharma- cogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics, 6, 243–250.CrossRefPubMedGoogle Scholar
  19. Lencz, T., Szeszko, P. R., DeRosse, P., Burdick, K. E., Bromet, E. J., Bilder, R. M., et al. (2010). A schizophrenia risk gene, ZNF804A, influences neuroanatomical and neurocognitive phenotypes. Neuropsychopharmacology, 35(11), 2284–2291. doi: 10.1038/npp.2010.102.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Liu, F., Guo, W., Yu, D., Gao, Q., Gao, K., Xue, Z., et al. (2012). Classification of different therapeutic responses of major depressive disorder with multivariate pattern analysis method based on structural MR scans. PloS One, 7(7), e40968. doi: 10.1371/journal.pone.0040968.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Liu, B., Zhang, X., Hou, B., Li, J., Qiu, C., Qin, W., et al. (2014). The impact of MIR137 on dorsolateral prefrontal-hippocampal functional connectivity in healthy subjects. Neuropsychopharmacology, 39(9), 2153–2160. doi: 10.1038/npp.2014.63.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Mannisto, P. T., & Kaakkola, S. (1999). Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacological Reviews, 51(4), 593–628.PubMedGoogle Scholar
  23. Meyer-Lindenberg, A., Kohn, P. D., Kolachana, B., Kippenhan, S., McInerney-Leo, A., Nussbaum, R., et al. (2005). Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nature Neuroscience, 8(5), 594–596. doi: 10.1038/nn1438.CrossRefPubMedGoogle Scholar
  24. Noh, J. S., Kim, E. Y., Kang, J. S., Kim, H. R., Oh, Y. J., & Gwag, B. J. (1999). Neurotoxic and neuroprotective actions of catecholamines in cortical neurons. Experimental Neurology, 159(1), 217–224. doi: 10.1006/exnr.1999.7144.CrossRefPubMedGoogle Scholar
  25. O’Donovan, M. C., Craddock, N., Norton, N., Williams, H., Peirce, T., Moskvina, V., et al. (2008). Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genetics, 40(9), 1053–1055. doi: 10.1038/ng.201.CrossRefPubMedGoogle Scholar
  26. Oldfield, R. C. (1971). The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia, 9(1), 97–113.CrossRefPubMedGoogle Scholar
  27. Owen, A. M., McMillan, K. M., Laird, A. R., & Bullmore, E. (2005). N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Human Brain Mapping, 25, 46–59.CrossRefPubMedGoogle Scholar
  28. Purcell, S. M., Wray, N. R., Stone, J. L., Visscher, P. M., O’Donovan, M. C., Sullivan, P. F., et al. (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature, 460(7256), 748–752. doi: 10.1038/nature08185.PubMedGoogle Scholar
  29. Qin, S., Cousijn, H., Rijpkema, M., Luo, J., Franke, B., Hermans, E. J., et al. (2012). The effect of moderate acute psychological stress on working memory-related neural activity is modulated by a genetic variation in catecholaminergic function in humans. Frontiers in Integrative Neuroscience, 6, 16. doi: 10.3389/fnint.2012.00016.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Riley, B., Thiselton, D., Maher, B. S., Bigdeli, T., Wormley, B., McMichael, G. O., et al. (2010). Replication of association between schizophrenia and ZNF804A in the Irish case-control study of schizophrenia sample. Molecular Psychiatry, 15(1), 29–37. doi: 10.1038/mp.2009.109.CrossRefPubMedGoogle Scholar
  31. Schultz, C. C., Nenadic, I., Riley, B., Vladimirov, V. I., Wagner, G., Koch, K., et al. (2014). ZNF804A and cortical structure in schizophrenia: in vivo and postmortem studies. Schizophrenia Bulletin, 40(3), 532–541. doi: 10.1093/schbul/sbt123.CrossRefPubMedGoogle Scholar
  32. Seamans, J. K., & Yang, C. R. (2004). The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Progress in Neurobiology, 74(1), 1–58. doi: 10.1016/j.pneurobio.2004.05.006.CrossRefPubMedGoogle Scholar
  33. Szeszko, P. R., Lipsky, R., Mentschel, C., Robinson, D., Gunduz-Bruce, H., Sevy, S., et al. (2005). Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Molecular Psychiatry, 10(7), 631–636. doi: 10.1038/sj.mp.4001656.CrossRefPubMedGoogle Scholar
  34. Thomas, G., Sinville, R., Sutton, S., Farquar, H., Hammer, R. P., Soper, S. A., et al. (2004). Capillary and microelectrophoretic separations of ligase detection reaction products produced from low-abundant point mutations in genomic DNA. Electrophoresis, 25, 1668–1677.CrossRefPubMedGoogle Scholar
  35. Tian, T., Qin, W., Liu, B., Wang, D., Wang, J., Jiang, T., et al. (2013). Catechol-O-methyltransferase Val158Met polymorphism modulates gray matter volume and functional connectivity of the default mode network. PloS One, 8(10), e78697. doi: 10.1371/journal.pone.0078697.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Walton, E., Turner, J., Gollub, R. L., Manoach, D. S., Yendiki, A., Ho, B. C., et al. (2013). Cumulative genetic risk and prefrontal activity in patients with schizophrenia. Schizophrenia Bulletin, 39(3), 703–711. doi: 10.1093/schbul/sbr190.CrossRefPubMedGoogle Scholar
  37. Wei, Q., Li, M., Kang, Z., Li, L., Diao, F., Zhang, R., et al. (2015). ZNF804A rs1344706 is associated with cortical thickness, surface area, and cortical volume of the unmedicated first episode schizophrenia and healthy controls. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 168B(4), 265–273. doi: 10.1002/ajmg.b.32308.CrossRefGoogle Scholar
  38. Williams, H. J., Norton, N., Dwyer, S., Moskvina, V., Nikolov, I., Carroll, L., et al. (2011). Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. [research support, N.I.H., extramural research support, non-U.S. Gov’t]. Molecular Psychiatry, 16(4), 429–441. doi: 10.1038/mp.2010.36.CrossRefPubMedGoogle Scholar
  39. Winkler, A. M., Kochunov, P., Blangero, J., Almasy, L., Zilles, K., Fox, P. T., et al. (2010). Cortical thickness or grey matter volume? The importance of selecting the phenotype for imaging genetics studies. NeuroImage, 53(3), 1135–1146. doi: 10.1016/j.neuroimage.2009.12.028.CrossRefPubMedGoogle Scholar
  40. Xiao, X., Luo, X. J., Chang, H., Liu, Z., & Li, M. (2016). Evaluation of European schizophrenia GWAS loci in Asian populations via comprehensive meta-analyses. Molecular Neurobiology. doi: 10.1007/s12035-016-9990-3.Google Scholar
  41. Yi, P., Chen, Z., Zhao, Y., Guo, J., Fu, H., Zhou, Y., et al. (2009). PCR/LDR/capillary electrophoresis for detection of single-nucleotide differences between fetal and maternal DNA in maternal plasma. Prenatal Diagnosis, 29(3), 217–222. doi: 10.1002/pd.2072.CrossRefPubMedGoogle Scholar
  42. Zhao, F., Zhang, X., Qin, W., Liu, F., Wang, Q., Xu, Q., et al. (2015). Network-dependent modulation of COMT and DRD2 polymorphisms in healthy young adults. Scientific Reports, 5, 17996. doi: 10.1038/srep17996.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Qiang Xu
    • 1
  • Yongqin Xiong
    • 1
  • Congcong Yuan
    • 1
  • Feng Liu
    • 1
  • Fangshi Zhao
    • 1
  • Junlin Shen
    • 1
  • Wen Qin
    • 1
  • Chunshui Yu
    • 1
  1. 1.Department of Radiology and Tianjin Key Laboratory of Functional ImagingTianjin Medical University General HospitalTianjinChina

Personalised recommendations