Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk
Open accessAbstract
We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 x 10(-7); OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes.
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Egr3 has been implicated in both schizophrenia and circadian organization.
“Another gene that has been implicated in both SZ and circadian organization is immediate early gene growth response 3 (Egr3)162,165–168.”
From Circadian rhythm disruption and mental health (2020) · cites this paper as [165]
The Introduction links EGR3 to schizophrenia susceptibility. The Discussion mentions EGR3 in a study of circadian rhythm-related genes, but does not establish a role for EGR3 in circadian organization. Page numbers were not supplied for these passages. (LLM, conf=0.86)
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The Sequence Alignment/Map format and SAMtools
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., & 1000 Genome Project Data Processing Subgroup (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp352 · Cited by 62,041 · see citing works
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · cited 1× · see citing works
“07 [36], and the Fisher test with 95% confidence intervals.”
MethodHaploview: analysis and visualization of LD and haplotype maps
Barrett, J., Fry, B., Maller, J., & Daly, M. (2005) · Bioinform. · doi:10.1093/bioinformatics/bth457 · Cited by 15,086 · cited 1× · see citing works
“Haploview [37] was used to estimate LD between SNPs across the ARC region in the CEPH population (Utah residents with ancestry from northern and western Europe, abbreviated CEU), Hapmap [38] data release 28.”
MethodAn integrated map of genetic variation from 1,092 human genomes
The 1000 Genomes Project Consortium (2012) · Nature · doi:10.1038/nature11632 · Cited by 7,711 · see citing works
A second generation human haplotype map of over 3.1 million SNPs
The International HapMap Consortium (2007) · Nature · doi:10.1038/nature06258 · Cited by 4,438 · cited 1× · see citing works
“Haploview [37] was used to estimate LD between SNPs across the ARC region in the CEPH population (Utah residents with ancestry from northern and western Europe, abbreviated CEU), Hapmap [38] data release 28.”
Method(2013) · The Lancet · doi:10.1016/s0140-6736(12)62129-1 · Cited by 3,010 · see citing works
Schizophrenia as a Complex Trait: Evidence From a Meta-analysis of Twin Studies
Sullivan, P. F., Kendler, K. S., & Neale, M. C. (2003) · Archives of General Psychiatry · doi:10.1001/archpsyc.60.12.1187 · Cited by 2,356 · cited 1× · see citing works
“The genetic contribution to schizophrenia risk ranges from 50–80% [1, 3].”
BackgroundLichtenstein, P., Yip, B. H., Björk, C., Pawitan, Y., Cannon, T. D., Sullivan, P. F., & Hultman, C. M. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60072-6 · Cited by 2,125 · see citing works
Purcell, S., Cherny, S. S., & Sham, P. C. (2003) · Bioinformatics · doi:10.1093/bioinformatics/19.1.149 · Cited by 2,057 · see citing works
Neuregulin 1 and Susceptibility to Schizophrenia
Stefánsson, H., Pétursson, H., Sigurðsson, E., Steinthórsdóttir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., Brynjolfsson, J., Gunnarsdottir, S., Ivarsson, O., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/342734 · Cited by 1,671 · see citing works
De novo mutations in schizophrenia implicate synaptic networks
Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D. M., et al. (2014) · Nature · doi:10.1038/nature12929 · Cited by 1,617 · see citing works
A polygenic burden of rare disruptive mutations in schizophrenia
Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O’Dushlaine, C., Chambert, K., Bergen, S. E., Kähler, A., et al. (2014) · Nature · doi:10.1038/nature12975 · Cited by 1,385 · cited 1× · see citing works
“And exome sequencing has identified rare disruptive mutations involving proteins that associate with ARC are more prevalent in schizophrenia patients than controls [29].”
BackgroundA Nerve Growth Factor-Induced Gene Encodes a Possible Transcriptional Regulatory Factor
Milbrandt, J. (1987) · Science · doi:10.1126/science.3672127 · Cited by 1,202 · cited 1× · see citing works
“The early growth response gene (EGR) family of IEG transcription factors is involved in numerous neural processes, including regulation of synaptic proteins and synaptic plasticity, dysfunction of which have been hypothesized to play a role in schizophrenia pathogenesis [4–10].”
BackgroundGenome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia
Lewis, C. M., Levinson, D. F., Wise, L. H., DeLisi, L. E., Straub, R. E., Hovatta, I., Williams, N. M., Schwab, S. G., Pulver, A. E., Faraone, S. V., et al. (2003) · The American Journal of Human Genetics · doi:10.1086/376549 · Cited by 1,134 · see citing works
Self-citationNMDA receptor hypofunction model of schizophrenia
Olney, J. W., Newcomer, J. W., & Farber, N. B. (1999) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(99)00029-1 · Cited by 1,020 · cited 1× · see citing works
“EGR3 is regulated downstream of several key schizophrenia candidate proteins, including Neuregulin 1, N-methyl D-Aspartate Receptors (NMDARs) and calcineurin (CN) [11, 16–21], and Egr3KOmice share key phenotypes with NMDARKO and CNKO mice, including memory dysfunction and deficits in the form of hippocampal synaptic p…”
BackgroundJones, M. W., Errington, M. L., French, P. J., Fine, A., Bliss, T., Garel, S., Charnay, P., Bozon, B., Laroche, S., & Davis, S. (2001) · Nature Neuroscience · doi:10.1038/85138 · Cited by 899 · see citing works
Kirov, G., Pocklington, A. J., Holmans, P., Ivanov, D., Ikeda, M., Ruderfer, D., Moran, J., Chambert, K., Toncheva, D., Georgieva, L., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.154 · Cited by 844 · see citing works
Arc/Arg3.1 Is Essential for the Consolidation of Synaptic Plasticity and Memories
Plath, N., Ohana, O., Dammermann, B., Errington, M. L., Schmitz, D., Gross, C., Mao, X., Engelsberg, A., Mahlke, C., Welzl, H., et al. (2006) · Neuron · doi:10.1016/j.neuron.2006.08.024 · Cited by 827 · see citing works
Zeng, H., Chattarji, S., Barbarosie, M., Rondi-Reig, L., Philpot, B. D., Miyakawa, T., Bear, M. F., & Tonegawa, S. (2001) · Cell · doi:10.1016/s0092-8674(01)00585-2 · Cited by 498 · see citing works
Verde, E. R., Lee‐Osbourne, J., Worley, P. F., Malinow, R., & Cline, H. T. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.031 · Cited by 403 · see citing works
Fahmy, R. G., Dass, C. R., Sun, L., Chesterman, C. N., & Khachigian, L. M. (2003) · Nature Medicine · doi:10.1038/nm905 · Cited by 361 · cited 1× · see citing works
“The early growth response gene (EGR) family of IEG transcription factors is involved in numerous neural processes, including regulation of synaptic proteins and synaptic plasticity, dysfunction of which have been hypothesized to play a role in schizophrenia pathogenesis [4–10].”
BackgroundIdentification of genetic variants using bar-coded multiplexed sequencing
Craig, D. W., Pearson, J. V., Szelinger, S., Sekar, A., Redman, M., Corneveaux, J. J., Pawlowski, T. L., Laub, T., Nunn, G. B., Stephan, D. A., et al. (2008) · Nature Methods · doi:10.1038/nmeth.1251 · Cited by 301 · see citing works
Self-citationMeta-analysis of 32 genome-wide linkage studies of schizophrenia
Ng, M., Levinson, D. F., Faraone, S. V., Suarez, B. K., DeLisi, L. E., Arinami, T., Riley, B. P., Paunio, T., Pulver, A. E., Irmansyah, et al. (2008) · Molecular Psychiatry · doi:10.1038/mp.2008.135 · Cited by 279 · cited 1× · see citing works
“The importance of this region in schizophrenia is also supported by meta- analysis of 32 GenomeWide Linkage studies [59] and rank-based genome scan meta-analysis from 20 schizophrenia genome scans [60].”
MethodRace and risk of schizophrenia in a US birth cohort: another example of health disparity?
Bresnahan, M., Begg, M., Brown, A. S., Schaefer, C., Sohler, N., Insel, B. J., Vella, L., & Susser, E. (2007) · International Journal of Epidemiology · doi:10.1093/ije/dym041 · Cited by 273 · cited 1× · see citing works
“Interestingly, rates of schizophrenia have been reported to be up to three times higher in AA than EU individuals, which may be due to differences in both genetic and environmental causes [61].”
BackgroundArc/Arg3.1: Linking Gene Expression to Synaptic Plasticity and Memory
Tzingounis, A. V., & Nicoll, R. A. (2006) · Neuron · doi:10.1016/j.neuron.2006.10.016 · Cited by 246 · see citing works
Li, L., Carter, J., Gao, X., Whitehead, J., & Tourtellotte, W. G. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.23.10286-10300.2005 · Cited by 235 · cited 2× · see citing works
“If so, then dysfunction of the gene activity-regulated cytoskeleton-associated protein (ARC) [24], which is a downstream target of EGR3 and is similarly required for memory formation and hippocampal LTD in mice [25–27], may also confer risk for schizophrenia.”
BackgroundMechtcheriakova, D., Wlachos, A., Holzmüller, H., Binder, B. R., & Hofer, E. (1999) · Blood · doi:10.1182/blood.v93.11.3811 · Cited by 227 · see citing works
Tabarés-Seisdedos, R., & Rubenstein, J. L. R. (2009) · Molecular Psychiatry · doi:10.1038/mp.2009.2 · Cited by 225 · see citing works
Signals that determine Schwann cell identity*
Jessen, K. R., & Mirsky, R. (2002) · Journal of Anatomy · doi:10.1046/j.1469-7580.2002.00046.x · Cited by 210 · cited 1× · see citing works
“The early growth response gene (EGR) family of IEG transcription factors is involved in numerous neural processes, including regulation of synaptic proteins and synaptic plasticity, dysfunction of which have been hypothesized to play a role in schizophrenia pathogenesis [4–10].”
BackgroundA statistical method for the detection of variants from next-generation resequencing of DNA pools
Bansal, V. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq214 · Cited by 186 · see citing works
Yamada, K., Gerber, D. J., Iwayama, Y., Ohnishi, T., Ohba, H., Toyota, T., Aruga, J., Minabe, Y., Tonegawa, S., & Yoshikawa, T. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0610765104 · Cited by 163 · see citing works
Cyclosporin A-Sensitive Transcription Factor Egr-3 Regulates Fas Ligand Expression
Mittelstadt, P. R., & Ashwell, J. D. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.7.3744 · Cited by 163 · cited 1× · see citing works
“This pathway, triggered by activity-dependent opening of NMDARs, allows neuronal calcium influx, which acts on CN, a Ca++ activated phosphatase, to activate expression of the IEG transcription factor EGR3 [19, 21].”
BackgroundStructural Basis of Arc Binding to Synaptic Proteins: Implications for Cognitive Disease
Zhang, W., Wu, J., Ward, M. D., Yang, S., Chuang, Y.-A., Xiao, M.-F., Li, R., Leahy, D. J., & Worley, P. F. (2015) · Neuron · doi:10.1016/j.neuron.2015.03.030 · Cited by 162 · cited 1× · see citing works
“Recent high-profile studies of rare copy number variations (CNVs) and de novo variations enriched in schizophrenia patients have identified the importance of proteins that complex with ARC protein in the post-synaptic density in the risk for schizophrenia [28–30, 45].”
BackgroundMansour, H. A., Talkowski, M. E., Wood, J., Chowdari, K. V., McClain, L., Prasad, K., Montrose, D., Fagiolini, A., Friedman, E. S., Allen, M. H., et al. (2009) · Bipolar Disorders · doi:10.1111/j.1399-5618.2009.00756.x · Cited by 161 · cited 2× · see citing works
“017), though this did not survive control for multiple comparisons [42].”
BackgroundA Novel microRNA and transcription factor mediated regulatory network in schizophrenia
Guo, A. Y., Sun, J., Jia, P., & Zhao, Z. (2010) · BMC Systems Biology · doi:10.1186/1752-0509-4-10 · Cited by 160 · cited 1× · see citing works
“In addition to the genetics findings, post mortem studies have reported reduced EGR3 mRNA levels in schizophrenia patients’ brains [11, 14], and a biomedical informatics study identified EGR3 as the central gene in a network of microRNAs and transcription factors implicated in schizophrenia pathogenesis [53].”
BackgroundA Role for Neuregulin1 Signaling in Muscle Spindle Differentiation
Hippenmeyer, S., Shneider, N. A., Birchmeier, C., Burden, S. J., Jessell, T. M., & Arber, S. (2002) · Neuron · doi:10.1016/s0896-6273(02)01101-7 · Cited by 155 · see citing works
Path Analysis of Qualitative Data on Pairs of Relatives: Application to Schizophrenia
Rao, D. C., Morton, N. E., Gottesman, I. I., & Lew, R. (1981) · Human Heredity · doi:10.1159/000153233 · Cited by 127 · see citing works
Leonard, S. S., Gault, J., Moore, T., Hopkins, J., Robinson, M., D, A. O. M., Adler, L. E., Cloninger, C. R., Kaufmann, C. A., Tsuang, M. T., et al. (1998) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19980710)81:4 · Cited by 127 · see citing works
Self-citationYamagata, K., Kaufmann, W. E., Lanahan, A. A., Papapavlou, M., Barnes, C. A., Andreasson, K. I., & Worley, P. F. (1994) · Learning & Memory · doi:10.1101/lm.1.2.140 · Cited by 103 · cited 1× · see citing works
“This pathway, triggered by activity-dependent opening of NMDARs, allows neuronal calcium influx, which acts on CN, a Ca++ activated phosphatase, to activate expression of the IEG transcription factor EGR3 [19, 21].”
BackgroundA calcineurin/AKAP complex is required for NMDA receptor-dependent long-term depression
Jurado, S., Biou, V., & Malenka, R. C. (2010) · Nature Neuroscience · doi:10.1038/nn.2613 · Cited by 101 · see citing works
The Role of DNA Copy Number Variation in Schizophrenia
Tam, G. W. C., Redon, R., Carter, N. P., & Grant, S. G. N. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.07.027 · Cited by 98 · see citing works
Mexal, S., Frank, M., Berger, R., Adams, C. E., Ross, R. G., Freedman, R., & Leonard, S. S. (2005) · Molecular Brain Research · doi:10.1016/j.molbrainres.2005.06.006 · Cited by 93 · cited 2× · see citing works
“In addition to the genetics findings, post mortem studies have reported reduced EGR3 mRNA levels in schizophrenia patients’ brains [11, 14], and a biomedical informatics study identified EGR3 as the central gene in a network of microRNAs and transcription factors implicated in schizophrenia pathogenesis [53].”
BackgroundThe immediate early gene early growth response gene 3 mediates adaptation to stress and novelty
Gallitano, A. L., Izumi, Y., Tokuda, K., Zorumski, C. F., Howell, M., Muglia, L. J., Wozniak, D. F., & Milbrandt, J. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.05.050 · Cited by 90 · see citing works
Self-citationSchrauwen, I., Sommen, M., Corneveaux, J. J., Reiman, R. A., Hackett, N. J., Claes, C., Claes, K., Bitner-Glindzicz, M. A. K., Coucke, P. J., Camp, G. V., et al. (2012) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.35737 · Cited by 71 · see citing works
Self-citationGallitano, A. L., Wozniak, D. F., Pehek, E. A., & Milbrandt, J. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301505 · Cited by 61 · see citing works
Self-citationJacobson, C., Duggan, D. J., & Fischbach, G. D. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404240101 · Cited by 59 · see citing works
The Neurobiology of the Stress Cascade and Its Potential Relevance for Schizophrenia
Corcoran, C. M., Gallitano, A. L., Leitman, D., & Malaspina, D. (2001) · Journal of Psychiatric Practice · doi:10.1097/00131746-200101000-00002 · Cited by 45 · cited 2× · see citing works
“The remaining influence may be attributed to environmental factors [2].”
BackgroundSelf-citationCommon risk genes for affective and schizophrenic psychoses
Maier, W. (2008) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-008-2008-z · Cited by 44 · see citing works
<i>EGR3</i> as a potential susceptibility gene for schizophrenia in Korea
Kim, S. H., Song, J. Y., Joo, E., Lee, K. Y., Ahn, Y. M., & Kim, Y. S. (2010) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31115 · Cited by 41 · see citing works
Fahmy, R. G., & Khachigian, L. M. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21145 · Cited by 34 · see citing works
Nishimura, Y., Takizawa, R., Koike, S., Kinoshita, A., Satomura, Y., Kawasaki, S., Yamasue, H., Tochigi, M., Kakiuchi, C., Sasaki, T., et al. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.08.021 · Cited by 33 · see citing works
Zhang, R., Lu, S., Meng, L., Min, Z., Tian, J., Valenzuela, R. K., Guo, T., Tian, L., Zhao, W., & Ma, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030237 · Cited by 30 · cited 2× · see citing works
“The EGR3 SNPs were not significant in the combined group of EU and AA samples (the CH samples were not included as EGR3 has previously been investigated for associations in this group [13]).”
BackgroundResultSelf-citationGenome-wide scan of homogeneous subtypes of NIMH genetics initiative schizophrenia families
Takahashi, S., Faraone, S. V., Lasky-Su, J. A., & Tsuang, M. T. (2005) · Psychiatry Research · doi:10.1016/j.psychres.2004.12.003 · Cited by 30 · see citing works
Genetic and functional analyses of early growth response (EGR) family genes in schizophrenia
Cheng, M.-C., Chuang, Y.-A., Lu, C.-L., Chen, Y.-J., Luu, S.-U., Li, J., Hsu, S.-H., & Chen, C. (2012) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.06.004 · Cited by 28 · see citing works
Kyogoku, C., Yanagi, M., Nishimura, K., Sugiyama, D., Morinobu, A., Fukutake, M., Maeda, K., Shirakawa, O., Kuno, T., & Kumagai, S. (2011) · Psychiatry Research · doi:10.1016/j.psychres.2009.11.003 · Cited by 20 · see citing works
Family-based association study of early growth response gene 3 with child bipolar I disorder
Gallitano, A. L., Tillman, R., Dinu, V., & Geller, B. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.01.011 · Cited by 19 · cited 3× · see citing works
“analysis of the EGR3 region has previously been published [43].”
BackgroundResultInfluentialSelf-citationNo association between EGR gene family polymorphisms and schizophrenia in the Chinese population
Liu, B., Zhang, J., Wang, L., Li, X.-W., Wang, Y., Ji, J., Yang, F., Wan, C., Gao, L., Xu, Y., et al. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.02.005 · Cited by 18 · see citing works
Holliday, E., Mowry, B. J., & Nyholt, D. (2008) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30722 · Cited by 10 · see citing works
A family-based association study of the EGR3 gene polymorphisms and schizophrenia
Qi-lan, N. I. N. G., Xu-Dong, M. A., Li-Zi, J. I. A. O., Niu, X., Li, J., Wang, B., Zhang, H., & Ma, J. (2012) · Hereditas (Beijing) · doi:10.3724/sp.j.1005.2012.00307 · Cited by 5 · cited 2× · see citing works
“This SNP was also reported in a haplotype associated with schizophrenia in a CH population [41].”
BackgroundSelf-citation宁启兰, Ma, J., 马旭东, 焦李子, 牛晓蓉, 李建鹏, 王彬, & 张欢 (2012) · Hereditas (Beijing) · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Circadian rhythm disruption and mental health
Walker, W. H., Walton, J. C., DeVries, A. C., & Nelson, R. J. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0694-0 · Cited by 1,030 · see citing works
Arc protein: a flexible hub for synaptic plasticity and cognition
Nikolaienko, O., Patil, S. S., Eriksen, M. S., & Bramham, C. R. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.09.006 · Cited by 183 · see citing works
Managò, F., Mereu, M., Mastwal, S. S., Mastrogiacomo, R., Scheggia, D., Emanuele, M., Luca, M. A. D., Weinberger, D. R., Wang, K. H., & Papaleo, F. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.07.044 · Cited by 117 · see citing works
“Arc chromosomal microdeletion and intragenic SNPs have also been found in association with neurodevelopmental disorders such as schizophrenia (Hu et al., 2015;Huentelman et al., 2015).”
BackgroundMereu, M., Contarini, G., Buonaguro, E. F., Latte, G., Managò, F., Iasevoli, F., de Bartolomeis, A., & Papaleo, F. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.04.037 · Cited by 66 · see citing works
Bradley, R. A., Shireman, J. M., McFalls, C., Choi, J., Canfield, S. G., Dong, Y. W., Liu, K. A., Lisota, B., Jones, J. R., Petersen, A. J., et al. (2019) · Development · doi:10.1242/dev.170910 · Cited by 64 · see citing works
“The DFB astrocytes had DEGs associated with behavioral disorders and drug addiction (FOSB and ARC) (Murphy et al., 2003), and schizophrenia (EGR1, EGR3 and ARC) (Duclot and Kabbaj, 2017; Huentelman et al., 2015).”
BackgroundWilkerson, J. R., Albanesi, J. P., & Huber, K. M. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.09.035 · Cited by 57 · see citing works
de Bartolomeis, A., Buonaguro, E. F., Latte, G., Rossi, R., Marmo, F., Iasevoli, F., & Tomasetti, C. (2017) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2017.00240 · Cited by 44 · see citing works
“Interestingly, an association of SNPs in Egr3 and Arc with schizophrenia has been proposed as a biological pathway of environmentally responsive, synaptic plasticity-related, schizophrenia risk genes (Huentelman et al., 2015).”
BackgroundOkuno, H., Minatohara, K., & Bito, H. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.09.025 · Cited by 43 · see citing works
Marballi, K. K., & Gallitano, A. L. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00023 · Cited by 40 · see citing works
Self-citationMätlik, K., Garton, D. R., Montaño-Rodriguez, A., Olfat, S., Eren, F., Casserly, L., Damdimopoulos, A. E., Panhelainen, A. E., Porokuokka, L. L., Kopra, J. J., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01554-2 · Cited by 39 · see citing works
Are Circadian Disturbances a Core Pathophysiological Component of Schizophrenia?
Delorme, T. C., Srivastava, L. K., & Cermakian, N. (2020) · Journal of Biological Rhythms · doi:10.1177/0748730420929448 · Cited by 38 · see citing works
Pfaffenseller, B., Magalhães, P. V. D. S., Bastiani, M. A. D., Castro, M. A. A., Gallitano, A. L., Kapczinski, F. P., & Klamt, F. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.78 · Cited by 31 · see citing works
Self-citationEGR3 Immediate Early Gene and the Brain-Derived Neurotrophic Factor in Bipolar Disorder
Pfaffenseller, B., Kapczinski, F. P., Gallitano, A. L., & Klamt, F. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00015 · Cited by 27 · see citing works
“…to neuronal plasticity, which has driven to the hypothesis that dysfunction in EGRs may be implicated in both the genetic and environmental involvement on psychiatric disorders susceptibility (Moises et al., 2002; Hanson and Gottesman, 2005; Gallitano et al., 2012; Huentelman et al., 2015).”
BackgroundInfluentialSelf-citationEtemadikhah, M., Niazi, A., Wetterberg, L., & Feuk, L. (2020) · Scientific Reports · doi:10.1038/s41598-020-57467-z · Cited by 27 · see citing works
Meyers, K. T., Marballi, K. K., Brunwasser, S. J., Renda, B., Charbel, M., Marrone, D. F., & Gallitano, A. L. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00092 · Cited by 26 · see citing works
“EGR3 has been associated with risk for schizophrenia in Japanese, Korean, Han Chinese, and US populations of European descent (Yamada et al., 2007; Kim et al., 2010; Zhang et al., 2012; Huentelman et al., 2015) and levels of EGR3 are reduced in the brains of schizophrenia patients (Mexal et al.”
BackgroundInfluentialSelf-citationPujol, C., Pellissier, L. P., Clément, C., Becker, J. A. J., & Merrer, J. L. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0247-y · Cited by 22 · see citing works
Penrod, R. D., Thomsen, M., Taniguchi, M., Guo, Y., Cowan, C. W., & Smith, L. N. (2019) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.172818 · Cited by 24 · see citing works
Marballi, K. K., Alganem, K., Brunwasser, S. J., Barkatullah, A., Meyers, K. T., Campbell, J. M., Ozols, A. B., McCullumsmith, R. E., & Gallitano, A. L. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02069-8 · Cited by 23 · see citing works
“Mol Cancer Res 2017; 15(9): 1184-1196.”
Self-citationGao, X., Grendel, J., Muhia, M., Castro‐Gomez, S., Süsens, U., Isbrandt, D., Kneussel, M., Kuhl, D., & Ohana, O. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.0623-19.2019 · Cited by 21 · see citing works
“Recent studies identified copy number variations (Kirov et al., 2012; Fernández et al., 2017), single nucleotide polymorphisms (Huentelman et al., 2015), and rare mutations (Fromer et al., 2014; Purcell et al., 2014) associated with high schizophrenia risk in genes whose products form complexes…”
BackgroundYe, Y., Mastwal, S. S., Cao, V. Y., Ren, M., Liu, Q., Zhang, W., ELKAHLOUN, A. G., & Wang, K. H. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhw181 · Cited by 17 · see citing works
Maple, A. M., Rowe, R. K., Lifshitz, J., Fernandez, F., & Gallitano, A. L. (2018) · Journal of Biological Rhythms · doi:10.1177/0748730418803802 · Cited by 17 · see citing works
Self-citationKhan, Z. U., Carretero‐Rey, M., de León-López, C. A. M., & Navarro‐Lobato, I. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05203-x · Cited by 19 · see citing works
“Additionally, some genetic variants of Arc are considered a risk factor for schizophrenia, increasing the risk of developing schizophrenia [333, 336].”
Mastwal, S. S., Cao, V. Y., & Wang, K. H. (2016) · Frontiers in Neural Circuits · doi:10.3389/fncir.2016.00100 · Cited by 15 · see citing works
“In parallel, Arc signaling complex has been shown as a target of mutations in neurodevelopmental psychiatric disorders such as schizophrenia (Fromer et al., 2014; Purcell et al., 2014; Hu et al., 2015; Huentelman et al., 2015).”
BackgroundArc controls alcohol cue relapse by a central amygdala mechanism
Pagano, R., Salamian, A., Zielinski, J., Beroun, A., Nalberczak‐Skóra, M., Skonieczna, E., Cały, A., Tay, N., Banaschewski, T., Desrivières, S., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01849-4 · Cited by 18 · see citing works
“In human studies, a correlation between ARC gene polymorphism was confirmed solely for schizophrenia and Alzheimer’s disease [63, 64] so far.”
BackgroundLoring, K. E., Mattiske, T., Lee, K., Zysk, A., Jackson, M. R., Noebels, J. L., & Shoubridge, C. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105329 · Cited by 15 · see citing works
“In PA2, these genes included Arc (a master regulator of synaptic plasticity, and associated with epilepsy and schizophrenia), and Nppa (a regulator of neuropeptide hormone activity) (Haug et al., 2000; Huentelman et al., 2015).”
Latusz, J., & Maćkowiak, M. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05362-5 · Cited by 15 · see citing works
Salem, N. M., Jack, K. M., Gu, H., Kumar, A., García, M., Yang, P., & Dinu, V. (2023) · Computer Methods and Programs in Biomedicine Update · doi:10.1016/j.cmpbup.2023.100106 · Cited by 14 · see citing works
Self-citationSchizophrenia: What’s Arc Got to Do with It?
Managò, F., & Papaleo, F. (2017) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2017.00181 · Cited by 14 · see citing works
“Moreover, an investigation on variants within the Arc gene reported a direct association between the rs35900184 single-nucleotide polymorphism (SNP) and schizophrenia (Huentelman et al., 2015).”
Meyers, K. T., Damphousse, C. C., Ozols, A. B., Campbell, J. M., Newbern, J. M., Hu, C., Marrone, D. F., & Gallitano, A. L. (2023) · Brain stimulation · doi:10.1016/j.brs.2023.04.022 · Cited by 8 · see citing works
Self-citationArora, A., Jack, K. M., Kumar, A. V., Borad, M. J., Girardo, M. E., Filippis, E. D., Yang, P., & Dinu, V. (2023) · Journal of Racial and Ethnic Health Disparities · doi:10.1007/s40615-023-01867-0 · Cited by 7 · see citing works
Self-citationBreitborde, N. J. K., Maple, A. M., Bell, E. K., Dawson, S. C., Woolverton, C. B., Harrison‐Monroe, P., & Gallitano, A. L. (2016) · Schizophrenia Research · doi:10.1016/j.schres.2016.12.005 · Cited by 5 · see citing works
“For the current study, we focused on the role of ARC in moderating response to CR given (i) its association with schizophrenia susceptibility (Huentelman et al., 2015) and (ii) evidence supporting a putative role of ARC in translating environmental learning events (e.g., CR exercises) into changes…”
BackgroundMethodSelf-citationDNA methylation analysis of the EGR3 gene in patients of schizophrenia
Hu, T., Hsu, S.-H., Tsai, S.-M., & Cheng, M.-C. (2017) · Psychiatry Research · doi:10.1016/j.psychres.2017.02.014 · Cited by 5 · see citing works
“The EGR3 is abnormally expressed in the brains of schizophrenic patients and is considered a susceptibility gene for schizophrenia (Huentelman et al., 2015; Yamada et al., 2007), but evident discourages the actual association of the EGR3 in schizophrenia (Cheng et al., 2012).”
BackgroundTranscription Factors in Schizophrenia: A Current View of Genetic Aspects
Zakharyan, R. (2016) · Scientific Journal of Genetics and Gene Therapy · doi:10.17352/sjggt.000010 · Cited by 5 · see citing works
“So far, in a pooled study of biological pathways of schizophrenia risk it has been shown that the EGR3 gene rs1877670 SNP is associated with disease [25].”
BackgroundKobayashi, H., Yasukochi, M., Horie, M., Orba, Y., Sawa, H., Fujino, K., & Taharaguchi, S. (2024) · PLoS ONE · doi:10.1371/journal.pone.0314980 · Cited by 4 · see citing works
Bristot, G., Feiten, J. G., Pfaffenseller, B., Hizo, G. H., Possebon, G. M. P., Valiati, F. E., Pinto, J. V., Caldieraro, M. A., Fleck, M. P. D. A., Gama, C. S., et al. (2024) · Trends in Psychiatry and Psychotherapy · doi:10.47626/2237-6089-2023-0749 · Cited by 3 · see citing works
“29 In this study, EGR1, EGR3, and CRY2 were selected based on their potential to mediate gene-environment effects on psychopathology and based on previously reported association with psychiatric disorders, 5,11,12,24,28,30-33 including studies from our group.”
The role and molecular mechanisms of the early growth response 3 gene in schizophrenia
He, Q., Li, R., Zhong, N., Ma, J., Nie, F., & Zhang, R. (2024) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32969 · Cited by 2 · see citing works
“Huentelman et al. reported an association between EGR3 and schizophrenia in the US population of European descent but not in the African-American population (Huentelman et al., 2015).”
BackgroundSelf-citationNeuropsychopharmARCology: Shaping Neuroplasticity through Arc/ Arg3.1 Modulation
Mottarlini, F., Caffino, L., Fumagalli, F., Calabrese, F., & Brivio, P. (2024) · Current Neuropharmacology · doi:10.2174/011570159x338335240903075655 · Cited by 2 · see citing works
“1 gene and schizophrenia [49].”
Grønli, J., Schmidt, M. A., & Wisor, J. P. (2018) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2018.00036 · Cited by 2 · see citing works
“Functional polymorphisms in Egr3 and its regulatory targets such as Arc may prove useful biomarkers for sensitivity to the negative impacts of sleepiness on cognition, as they have for symptoms of schizophrenia risk (Huentelman et al., 2015).”
BackgroundInfluentialUnderstanding Schizophrenia: Genetic Causes and Treatment
Javeria, F., Altaf, S., Zair, A., & Iqbal, R. K. (2019) · Current Neuropsychiatry and Clinical Neuroscience Reports · doi:10.33702/cncnr.2019.1.1.2 · Cited by 2 · see citing works
Pine, J. G., Moe, A. M., Maple, A. M., Gallitano, A. L., & Breitborde, N. J. K. (2020) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2020.101974 · Cited by 2 · see citing works
Self-citationLancaster, H. S., Dinu, V., Arora, A., Li, J., & Gruen, J. R. (2021) · medRxiv · doi:10.1101/2021.08.24.21262573 · Cited by 2 · see citing works
Self-citationVastrad, B. M., & Vastrad, C. M. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.29.489994 · Cited by 2 · see citing works
Satterfield, B. C., Finlay, M., Fluke, S. K., Skeiky, L., Schmidt, M. A., Wisor, J. P., & Dongen, H. P. A. V. (2025) · SLEEP Advances · doi:10.1093/sleepadvances/zpaf041 · Cited by 1 · see citing works
“The ancestral allele (C) was present at a frequency of 0.77 and the variant allele (T) was pre sent at a frequency of 0.23 in the study population, similar to that reported for healthy subjects in the published literature [ 35] and that of the global population.”
InfluentialRaaz, C. V., Bruce, L., Ganapathiraju, M. K., Klein‐Seetharaman, J., Liu, L., Dinu, V., Chapi, M., Kim, E., Kim, Y., White, T., et al. (2026) · Case Reports in Genetics · doi:10.1155/crig/9927839 · Cited by 1 · see citing works
Self-citationEGR3 Polymorphism Is a Potential Susceptibility Factor of Schizophrenia Risk in a Chinese Population
Bi, W., Li, J., Xiong, M., Nasifu, L., Tan, M., Tai, P., Jin, Q., Zhang, L., Zhu, C., & He, B. (2024) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2023.0562 · Cited by 1 · see citing works
“Furthermore, many studies have revealed that the polymorphisms in the EGR3 were investigated to be associated with SZ (Huentelman et al., 2015; Kim et al., 2010; Ning et al., 2012).”
Marballi, K. K., Alganem, K., Brunwasser, S. J., Barkatullah, A., Meyers, K. T., Campbell, J. M., Mccullumsmith, R. R., & Gallitano, A. L. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.09.01.276626
Self-citationA data-fusion approach to identifying developmental dyslexia from multi-omics datasetsPreprint
Carrion, J., Nandakumar, R., Shi, X., Gu, H., Kim, Y., Raskind, W. H., Peter, B., & Dinu, V. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.27.530280
“complex diseases and disabilities from a comprehensive perspective (1-21).”
BackgroundSelf-citationNandakumar, R., Shi, X., Gu, H., Kim, Y., Raskind, W. H., Peter, B., & Dinu, V. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.27.600448
Self-citationEGR3 Deletion Rescues Developmental and Epileptic Encephalopathy in Kcna1 -null MicePreprint
Mazumder, A. G., Karedia, S., Adhyapak, N., Schimer, C., Bass, J. S., Kamen, J. L., Jankovic, M. J., Miao, Q., Gallitano, A. L., Saltzman, A. B., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.07.658422
Self-citationVastrad, B. M., Pattanashetti, S., & Vastrad, C. M. (2025) · Advances in Biomarker Sciences and Technology · doi:10.1016/j.abst.2025.08.004
Transcription Factors in the Pathogenesis of Schizophrenia
Helaly, A. M., & Al‐Emam, A. (2026) · Life · doi:10.3390/life16050773
“The application of next-generation sequencing may be utilized worldwide to discover additional correlations [25].”
- Authors
- Huentelman, M. J., Muppana, L., Corneveaux, J. J., Dinu, V., Pruzin, J. J., Reiman, R., Borish, C. N., De Both, M., Ahmed, A., Todorov, A., Cloninger, C. R., Zhang, R., Ma, J., & Gallitano, A. L.
- Affiliations
- Translational Genomics Research Institute (US)
- University of Arizona College of Medicine- Phoenix (US)
- Arizona State University (US)
- Washington University in St. Louis (US)
- Xi'an Honghui Hospital (CN)
- Xi'an Jiaotong University (CN)
- Corresponding author
- Gallitano, Amelia L.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-10-16
- Volume
- 10
- Issue
- 10
- Pages
- e0135076
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4608790
- OpenAlex
- W2157400934
- Cited by
- 52
- References
- 61
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 5 · 2018: 6 · 2017: 8 · 2016: 6
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Arizona State University Library Digital Repository (Arizona State University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Pfizer
- Arizona Department of Health Services
- National Alliance for Research on Schizophrenia and Depression (MH097803)
- National Institutes of Health (NIH-R01)
- Fundamental Research Funds for the Central Universities (XJJ2012124, 2012JDGZ07)
- National Institute of Mental Health (MH097803, R01MH083823, U01MH046276, R01MH097803, R01MH067921, R01 MH-)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, EGR3, Arc, single nucleotide polymorphisms, genetic susceptibility, synaptic plasticity, immediate early genes, gene-environment interaction, African ancestry, European ancestry, Han Chinese
- MeSH terms
- China, Cytoskeletal Proteins, Female, Humans, Male, Nerve Tissue Proteins, Risk Factors, Schizophrenia, Polymorphism, Single Nucleotide, Asian People, Early Growth Response Protein 3, High-Throughput Nucleotide Sequencing, Genotyping Techniques
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