Hostname: page-component-8448b6f56d-tj2md Total loading time: 0 Render date: 2024-04-23T15:54:49.908Z Has data issue: false hasContentIssue false
  • English
  • Français

ZNF804A genetic variation (rs1344706) affects brain grey but not white matter in schizophrenia and healthy subjects

Published online by Cambridge University Press:  20 May 2014

I. Nenadic ,
R. Maitra ,
F. B. Basmanav ,
C. C. Schultz ,
C. Lorenz ,
C. Schachtzabel ,
S. Smesny ,
M. M. Nöthen ,
S. Cichon  and
J. R. Reichenbach
...Show all authors
I. Nenadic*
Affiliation:
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
R. Maitra
Affiliation:
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
F. B. Basmanav
Affiliation:
Institute of Human Genetics, University of Bonn, Bonn, Germany
C. C. Schultz
Affiliation:
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
C. Lorenz
Affiliation:
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
C. Schachtzabel
Affiliation:
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
S. Smesny
Affiliation:
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
M. M. Nöthen
Affiliation:
Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
S. Cichon
Affiliation:
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland
J. R. Reichenbach
Affiliation:
Medical Physics Group, Institute for Diagnostic and Interventional Radiology I (IDIR I), Jena University Hospital, Germany
H. Sauer
Affiliation:
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
R. G. M. Schlösser
Affiliation:
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
C. Gaser
Affiliation:
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany Department of Neurology, Jena University Hospital, Jena, Germany
*
*Address for correspondence: I. Nenadic, M.D., Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07743 Jena, Germany. (Email: igor.nenadic@uni-jena.de)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Genetic variation in the gene encoding ZNF804A, a risk gene for schizophrenia, has been shown to affect brain functional endophenotypes of the disorder, while studies of white matter structure have been inconclusive.

Method

We analysed effects of ZNF804A single nucleotide polymorphism rs1344706 on grey and white matter using voxel-based morphometry (VBM) in high-resolution T1-weighted magnetic resonance imaging scans of 62 schizophrenia patients and 54 matched healthy controls.

Results

We found a significant (p < 0.05, family-wise error corrected for multiple comparisons) interaction effect of diagnostic group x genotype for local grey matter in the left orbitofrontal and right and left lateral temporal cortices, where patients and controls showed diverging effects of genotype. Analysing the groups separately (at p < 0.001, uncorrected), variation in rs1344706 showed effects on brain structure within the schizophrenia patients in several areas including the left and right inferior temporal, right supramarginal/superior temporal, right and left inferior frontal, left frontopolar, right and left dorsolateral/ventrolateral prefrontal cortices, and the right thalamus, as well as effects within the healthy controls in left lateral temporal, right anterior insula and left orbitofrontal cortical areas. We did not find effects of genotype of regional white matter in either of the two cohorts.

Conclusions

Our findings demonstrate effects of ZNF804A genetic variation on brain structure, with diverging regional effects in schizophrenia patients and healthy controls in frontal and temporal brain areas. These effects, however, might be dependent on the impact of other (genetic or non-genetic) disease factors.

Keywords

Cerebral cortexgenetic variationmagnetic resonance imagingpsychosisschizophreniavoxel-based morphometryZNF804A
Type
Original Articles
Information
Psychological Medicine , Volume 45 , Issue 1 , January 2015 , pp. 143 - 152
Copyright
Copyright © Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ashburner, J (2007). A fast diffeomorphic image registration algorithm. Neuroimage 38, 95–113.Google Scholar
Ashburner, J, Friston, KJ (2000). Voxel-based morphometry – the methods. Neuroimage 11, 805–821.Google Scholar
Ashburner, J, Friston, KJ (2005). Unified segmentation. Neuroimage 26, 839–851.Google Scholar
Bergmann, O, Haukvik, UK, Brown, AA, Rimol, LM, Hartberg, CB, Athanasiu, L, Melle, I, Djurovic, S, Andreassen, OA, Dale, AM, Agartz, I (2013). ZNF804A and cortical thickness in schizophrenia and bipolar disorder. Psychiatry Research 212, 154–157.CrossRefGoogle ScholarPubMed
Buonocore, F, Hill, MJ, Campbell, CD, Oladimeji, PB, Jeffries, AR, Troakes, C, Hortobagyi, T, Williams, BP, Cooper, JD, Bray, NJ (2010). Effects of cis-regulatory variation differ across regions of the adult human brain. Human Molecular Genetics 19, 4490–4496.Google Scholar
Cousijn, H, Rijpkema, M, Harteveld, A, Harrison, PJ, Fernandez, G, Franke, B, Arias-Vasquez, A (2012). Schizophrenia risk gene ZNF804A does not influence macroscopic brain structure: an MRI study in 892 volunteers. Molecular Psychiatry 17, 1155–1157.Google Scholar
Del Re, EC, Bergen, SE, Mesholam-Gately, RI, Niznikiewicz, MA, Goldstein, JM, Woo, TU, Shenton, ME, Seidman, LJ, McCarley, RW, Petryshen, TL (2014). Analysis of schizophrenia-related genes and electrophysiological measures reveals ZNF804A association with amplitude of P300b elicited by novel sounds. Translational Psychiatry 4, e346.Google Scholar
Donohoe, G, Morris, DW, Corvin, A (2010). The psychosis susceptibility gene ZNF804A: associations, functions, and phenotypes. Schizophrenia Bulletin 36, 904–909.CrossRefGoogle ScholarPubMed
Donohoe, G, Rose, E, Frodl, T, Morris, D, Spoletini, I, Adriano, F, Bernardini, S, Caltagirone, C, Bossu, P, Gill, M, Corvin, AP, Spalletta, G (2011). ZNF804A risk allele is associated with relatively intact gray matter volume in patients with schizophrenia. Neuroimage 54, 2132–2137.Google Scholar
Esslinger, C, Walter, H, Kirsch, P, Erk, S, Schnell, K, Arnold, C, Haddad, L, Mier, D, Opitz von Boberfeld, C, Raab, K, Witt, SH, Rietschel, M, Cichon, S, Meyer-Lindenberg, A (2009). Neural mechanisms of a genome-wide supported psychosis variant. Science 324, 605.Google Scholar
Girgenti, MJ, LoTurco, JJ, Maher, BJ (2012). ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2. PLOS ONE 7, e32404.Google ScholarPubMed
Hess, JL, Glatt, SJ (2014). How might ZNF804A variants influence risk for schizophrenia and bipolar disorder? A literature review, synthesis, and bioinformatic analysis. American Journal of Medical Genetics B: Neuropsychiatric Genetics 165, 28–40.CrossRefGoogle Scholar
Hill, MJ, Bray, NJ (2012). Evidence that schizophrenia risk variation in the ZNF804A gene exerts its effects during fetal brain development. American Journal of Psychiatry 169, 1301–1308.CrossRefGoogle ScholarPubMed
Ikuta, T, Peters, BD, Guha, S, John, M, Karlsgodt, KH, Lencz, T, Szeszko, PR, Malhotra, AK (2014). A schizophrenia risk gene, ZNF804A, is associated with brain white matter microstructure. Schizophrenia Research 155, 15–20.CrossRefGoogle ScholarPubMed
Lencz, T, Szeszko, PR, DeRosse, P, Burdick, KE, Bromet, EJ, Bilder, RM, Malhotra, AK (2010). A schizophrenia risk gene, ZNF804A, influences neuroanatomical and neurocognitive phenotypes. Neuropsychopharmacology 35, 2284–2291.CrossRefGoogle ScholarPubMed
Li, M, Shi, CJ, Shi, YY, Luo, XJ, Zheng, XB, Li, ZQ, Liu, JJ, Chong, SA, Lee, J, Wang, Y, Liu, XY, Yin, LD, Pu, XF, Diao, HB, Xu, Q, Su, B (2012). ZNF804A and schizophrenia susceptibility in Asian populations. American Journal of Medical Genetics B: Neuropsychiatric Genetics 159B, 794–802.Google Scholar
Linden, DE, Lancaster, TM, Wolf, C, Baird, A, Jackson, MC, Johnston, SJ, Donev, R, Thome, J (2013). ZNF804A genotype modulates neural activity during working memory for faces. Neuropsychobiology 67, 84–92.CrossRefGoogle ScholarPubMed
Mohnke, S, Erk, S, Schnell, K, Schutz, C, Romanczuk-Seiferth, N, Grimm, O, Haddad, L, Pohland, L, Garbusow, M, Schmitgen, MM, Kirsch, P, Esslinger, C, Rietschel, M, Witt, SH, Nothen, MM, Cichon, S, Mattheisen, M, Muhleisen, T, Jensen, J, Schott, BH, Maier, W, Heinz, A, Meyer-Lindenberg, A, Walter, H (2014). Further evidence for the impact of a genome-wide-supported psychosis risk variant in ZNF804A on the theory of mind network. Neuropsychopharmacology 39, 1196–1205.Google Scholar
O'Donoghue, T, Morris, DW, Fahey, C, Da Costa, A, Moore, S, Cummings, E, Leicht, G, Karch, S, Hoerold, D, Tropea, D, Foxe, JJ, Gill, M, Corvin, A, Donohoe, G (2014). Effects of ZNF804A on auditory P300 response in schizophrenia. Translational Psychiatry 4, e345.Google Scholar
O'Donovan, MC, Craddock, N, Norton, N, Williams, H, Peirce, T, Moskvina, V, Nikolov, I, Hamshere, M, Carroll, L, Georgieva, L, Dwyer, S, Holmans, P, Marchini, JL, Spencer, CC, Howie, B, Leung, HT, Hartmann, AM, Möller, HJ, Morris, DW, Shi, Y, Feng, G, Hoffmann, P, Propping, P, Vasilescu, C, Maier, W, Rietschel, M, Zammit, S, Schumacher, J, Quinn, EM, Schulze, TG, Williams, NM, Giegling, I, Iwata, N, Ikeda, M, Darvasi, A, Shifman, S, He, L, Duan, J, Sanders, AR, Levinson, DF, Gejman, PV, Cichon, S, Nothen, MM, Gill, M, Corvin, A, Rujescu, D, Kirov, G, Owen, MJ, Buccola, NG, Mowry, BJ, Freedman, R, Amin, F, Black, DW, Silverman, JM, Byerley, WF, Cloninger, CR; Molecular Genetics of Schizophrenia Collaboration (2008). Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genetics 40, 1053–1055.Google Scholar
Okada, T, Hashimoto, R, Yamamori, H, Umeda-Yano, S, Yasuda, Y, Ohi, K, Fukumoto, M, Ikemoto, K, Kunii, Y, Tomita, H, Ito, A, Takeda, M (2012). Expression analysis of a novel mRNA variant of the schizophrenia risk gene ZNF804A . Schizophrenia Research 141, 277–278.Google Scholar
Paulus, FM, Krach, S, Bedenbender, J, Pyka, M, Sommer, J, Krug, A, Knake, S, Nothen, MM, Witt, SH, Rietschel, M, Kircher, T, Jansen, A (2013). Partial support for ZNF804A genotype-dependent alterations in prefrontal connectivity. Human Brain Mapping 34, 304–313.Google Scholar
Rasetti, R, Sambataro, F, Chen, Q, Callicott, JH, Mattay, VS, Weinberger, DR (2011). Altered cortical network dynamics: a potential intermediate phenotype for schizophrenia and association with ZNF804A . Archives of General Psychiatry 68, 1207–1217.Google Scholar
Schultz, CC, Nenadic, I, Riley, B, Vladimirov, VI, Wagner, G, Koch, K, Schachtzabel, C, Muhleisen, TW, Basmanav, B, Nothen, MM, Deufel, T, Kiehntopf, M, Rietschel, M, Reichenbach, JR, Cichon, S, Schlosser, RG, Sauer, H (2014). ZNF804A and cortical structure in schizophrenia: in vivo and postmortem studies. Schizophrenia Bulletin 40, 532–541.Google Scholar
Schwab, SG, Kusumawardhani, AA, Dai, N, Qin, W, Wildenauer, MD, Agiananda, F, Amir, N, Antoni, R, Arsianti, T, Asmarahadi, A, Diatri, H, Djatmiko, P, Irmansyah, I, Khalimah, S, Kusumadewi, I, Kusumaningrum, P, Lukman, PR, Mustar, L, Nasrun, MW, Naswati, S, Prasetiyawan, P, Semen, GM, Siste, K, Tobing, H, Widiasih, N, Wiguna, T, Wulandari, WD; Indonesian Schizophrenia Genetics Consortium, Benyamin, B, Wildenauer, DB (2013). Association of rs1344706 in the ZNF804A gene with schizophrenia in a case/control sample from Indonesia. Schizophrenia Research 147, 46–52.Google Scholar
Sprooten, E, McIntosh, AM, Lawrie, SM, Hall, J, Sussmann, JE, Dahmen, N, Konrad, A, Bastin, ME, Winterer, G (2012). An investigation of a genomewide supported psychosis variant in ZNF804A and white matter integrity in the human brain. Magnetic Resonance Imaging 30, 1373–1380.Google Scholar
Sullivan, PF, Daly, MJ, O'Donovan, M (2012). Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nature Review Genetics 13, 537–551.Google Scholar
Thurin, K, Rasetti, R, Sambataro, F, Safrin, M, Chen, Q, Callicott, JH, Mattay, VS, Weinberger, DR (2013). Effects of ZNF804A on neurophysiologic measures of cognitive control. Molecular Psychiatry 18, 852–854.Google Scholar
Tzourio-Mazoyer, N, Landeau, B, Papathanassiou, D, Crivello, F, Etard, O, Delcroix, N, Mazoyer, B, Joliot, M (2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15, 273–289.CrossRefGoogle ScholarPubMed
Voineskos, AN, Lerch, JP, Felsky, D, Tiwari, A, Rajji, TK, Miranda, D, Lobaugh, NJ, Pollock, BG, Mulsant, BH, Kennedy, JL (2011). The ZNF804A gene: characterization of a novel neural risk mechanism for the major psychoses. Neuropsychopharmacology 36, 1871–1878.Google Scholar
Walter, H, Schnell, K, Erk, S, Arnold, C, Kirsch, P, Esslinger, C, Mier, D, Schmitgen, MM, Rietschel, M, Witt, SH, Nothen, MM, Cichon, S, Meyer-Lindenberg, A (2011). Effects of a genome-wide supported psychosis risk variant on neural activation during a theory-of-mind task. Molecular Psychiatry 16, 462–470.CrossRefGoogle ScholarPubMed
Wassink, TH, Epping, EA, Rudd, D, Axelsen, M, Ziebell, S, Fleming, FW, Monson, E, Ho, BC, Andreasen, NC (2012). Influence of ZNF804a on brain structure volumes and symptom severity in individuals with schizophrenia. Archives of General Psychiatry 69, 885–892.Google Scholar
Wei, Q, Kang, Z, Diao, F, Guidon, A, Wu, X, Zheng, L, Li, L, Guo, X, Hu, M, Zhang, J, Liu, C, Zhao, J (2013). No association of ZNF804A rs1344706 with white matter integrity in schizophrenia: a tract-based spatial statistics study. Neuroscience Letters 532, 64–69.Google Scholar
Wei, Q, Kang, Z, Diao, F, Shan, B, Li, L, Zheng, L, Guo, X, Liu, C, Zhang, J, Zhao, J (2012). Association of the ZNF804A gene polymorphism rs1344706 with white matter density changes in Chinese schizophrenia. Progress in Neuropsychopharmacology and Biological Psychiatry 36, 122–127.Google Scholar
Zhang, R, Yan, JD, Valenzuela, RK, Lu, SM, Du, XY, Zhong, B, Ren, J, Zhao, SH, Gao, CG, Wang, L, Guo, TW, Ma, J (2012). Further evidence for the association of genetic variants of ZNF804A with schizophrenia and a meta-analysis for genome-wide significance variant rs1344706. Schizophrenia Research 141, 40–47.Google Scholar
Supplementary material: File

Nenadic Supplementary Material

Figure S1

Download Nenadic Supplementary Material(File)
File 5.4 MB