Hostname: page-component-586b7cd67f-rdxmf Total loading time: 0 Render date: 2024-11-28T02:35:02.963Z Has data issue: false hasContentIssue false
  • English
  • Français

Allelic variants in the zinc transporter-3 gene, SLC30A3, a candidate gene identified from gene expression studies, show gender-specific association with schizophrenia

Published online by Cambridge University Press:  15 April 2020

C. Perez-Becerril ,
A.G. Morris ,
A. Mortimer ,
P.J. McKenna  and
J. de Belleroche
C. Perez-Becerril
Affiliation:
Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, United Kingdom
A.G. Morris
Affiliation:
Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, United Kingdom
A. Mortimer
Affiliation:
University of Hull and NAViGO, Hull, United Kingdom
P.J. McKenna
Affiliation:
Benito Menni Complex Assistencial en Salut Mental, Germanes Hospitalàries del Sagrat Cor de Jesús, C/Doctor Antoni Pujades 38-C, 08830 Sant Boi de Llobregat, Barcelona, Spain
J. de Belleroche*
Affiliation:
Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, United Kingdom
*
*Corresponding author. Neurogenetics Group, Brain Sciences Division, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. Tel.: +44 0 20 75 94 66 49. E-mail address: [email protected] (J. de Belleroche).
Get access

Abstract

Previous microarray analysis of gene expression in frontal cortex showed differential expression of genes associated with synaptic function in schizophrenia compared to matched-controls in two independent cohorts. One of these genes validated in both cohorts, SLC30A3, which encodes the Zinc Transporter 3 (ZNT3), is localised to synaptic vesicles in glutamate synapses and known to be involved in cognitive function. In view of the robust depletion of SLC30A3 mRNA in two independent studies and the importance of this gene in cognitive function, we investigated whether single nucleotide polymorphism (SNP) associations with schizophrenia could be detected in a UK case controlled schizophrenia cohort. Four SNPs were selected across this gene and genotyped in a cohort of cases and controls from East UK. We found significant associations with schizophrenia at the allelic (ORs: 1.51 to 1.57), genotype (ORs: 1.46 to 1.53) and haplotype level (P = 2.15 × 10−4). These associations proved to be gender-specific with significant effects of allele (ORs: 1.74 to 2.11), genotype (ORs: 1.78 to 2.14) and haplotype (P = 3.51 × 10−5) observed in female schizophrenia cases but not males, when split by gender. In conclusion, SNPs in SLC30A3 showed a gender-specific association with schizophrenia in this East UK cohort, which merits further investigation in other population samples.

Keywords

SchizophreniaCandidate gene associationsGender effects in schizophreniaSLC30A3Zinc transporter 3 (ZNT3)Synaptic plasticity
Type
Original article
Information
European Psychiatry , Volume 29 , Issue 3 , March 2014 , pp. 172 - 178
Copyright
Copyright © European Psychiatric Association 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.)

Footnotes

1

Both authors contributed equally to this work.

References

Adlard, PA, Parncutt, JM, Finkelstein, DI, Bush, AICognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer's disease? J Neurosci 2010;30:1631–1636.CrossRefGoogle ScholarPubMed
Amos, W, Driscoll, E, Hoffman, JICandidate genes versus genome-wide associations: which are better for detecting genetic susceptibility to infectious disease? Proc R Soc B Biol Sci 2011;278:1183–1188.CrossRefGoogle ScholarPubMed
Angermeyer, MC, Kuhn, LGender differences in age at onset of schizophrenia. An overview. Eur Arch Psychiatry Neurol Sci 1988;237:351–364.CrossRefGoogle ScholarPubMed
Barnes, MR, Huxley-Jones, J, Maycox, PR, Lennon, M, Thornber, A, Kelly, Fet al.Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia. J Neurosci Res 2011;89:1218–1227.CrossRefGoogle Scholar
Barrett, JC, Fry, B, Maller, J, Daly, MJHaploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21:263–265.CrossRefGoogle ScholarPubMed
Begemann, MJ, Dekker, CF, van Lunenburg, M, Sommer, IEEstrogen augmentation in schizophrenia: a quantitative review of current evidence. Schizophr Res 2012;141:179–184.CrossRefGoogle ScholarPubMed
Benjamini, Y, Hochberg, YControlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 1995;57:289–300.Google Scholar
Benjamini, Y, Yekutieli, DThe control of the false discovery rate in multiple testing under dependency. Ann Stat 2001;29:1165–1188.Google Scholar
Chissoe, S, Ehm, M, St., Jean P.Genes associated with schizophrenia. Patent Publication No. US 2008/0176239 A1:1–49.Google Scholar
Clarke, GM, Anderson, CA, Pettersson, FH, Cardon, LR, Morris, AP, Zondervan, KTBasic statistical analysis in genetic case-control studies. Nat Protoc 2011;6:121–133.CrossRefGoogle ScholarPubMed
Faul, F, Erdfelder, E, Lang, AG, Buchner, AG*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 2007;39:175–191.CrossRefGoogle ScholarPubMed
Hafner, H, Maurer, K, Loffler, W, Riecher-Rossler, AThe influence of age and sex on the onset and early course of schizophrenia. Br J Psychiatry 1993;162:80–86.CrossRefGoogle ScholarPubMed
Hanley, JAA heuristic approach to the formulas for population attributable fraction. J Epidemiol Community Health 2001;55:508–514.CrossRefGoogle ScholarPubMed
International Schizophrenia Consortium, Purcell, SM, Wray, NR, Stone, JL, Visscher, PM, O’Donovan, MCet al.Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460:748–752.CrossRefGoogle Scholar
Izumi, Y, Auberson, YP, Zorumski, CFZinc modulates bidirectional hippocampal plasticity by effects on NMDA receptors. J Neurosci 2006;26:7181–7188.CrossRefGoogle ScholarPubMed
Kim, B, Kim, H, Joo, YH, Lim, J, Kim, CY, Song, KSex-different association of DAO with schizophrenia in Koreans. Psychiatry Res 2010;179:121–125.CrossRefGoogle ScholarPubMed
Lee, JY, Kim, JH, Hong, SH, Lee, JY, Cherny, RA, Bush, AIet al.Estrogen decreases zinc transporter 3 expression and synaptic vesicle zinc levels in mouse brain. J Biol Chem 2004;279:8602–8607.CrossRefGoogle ScholarPubMed
Martel, G, Hevi, C, Friebely, O, Baybutt, T, Shumyatsky, GPZinc transporter 3 is involved in learned fear and extinction, but not in innate fear. Learn Mem 2010;17:582–590.CrossRefGoogle Scholar
Maycox, PR, Kelly, F, Taylor, A, Bates, S, Reid, J, Logendra, Ret al.Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function. Mol Psychiatry 2009;14:1083–1094.CrossRefGoogle ScholarPubMed
Mortimer, AM, McKenna, PJ, Lund, CE, Mannuzza, SRating of negative symptoms using the High Royds Evaluation of Negativity (HEN) score. Br J Psychiatry 1989;Suppl. 7:89–92.CrossRefGoogle Scholar
Palmiter, RD, Cole, TB, Quaife, CJ, Findley, SDZnT-3, a putative transporter of zinc into synaptic vesicles. Proc Natl Acad Sci U S A 1996;93:14934–14939.CrossRefGoogle ScholarPubMed
Pan, E, Zhang, XA, Huang, Z, Krezel, A, Zhao, M, Tinberg, CEet al.Vesicular zinc promotes presynaptic and inhibits postsynaptic long-term potentiation of mossy fiber-CA3 synapse. Neuron 2011;71:1116–1126.CrossRefGoogle ScholarPubMed
Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MAR, Bender, Det al.PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81:559–575.CrossRefGoogle ScholarPubMed
Qian, J, Noebels, JLVisualization of transmitter release with zinc fluorescence detection at the mouse hippocampal mossy fibre synapse. J Physiol 2005;566:747–758.CrossRefGoogle ScholarPubMed
Ram Murthy, A, Purushottam, M, Kiran Kumar, HB, Vallikiran, M, Krishna, N, Jayramu Sriharsha, Ket al.Gender-specific association of TSNAX/DISC1 locus for schizophrenia and bipolar affective disorder in South Indian population. J Hum Genet 2012;e:1–8.Google Scholar
Ripke, S, Sanders, AR, Kendler, KS, Levinson, DF, Sklar, P, Holmans, PAet al.Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011;43:964–976.Google Scholar
Salazar, G, Craige, B, Love, R, Kalman, D, Faundez, VVglut1 and ZnT3 co-targeting mechanisms regulate vesicular zinc stores in PC12 cells. J Cell Sci 2005;118:1911–1921.CrossRefGoogle ScholarPubMed
Sensi, SL, Paoletti, P, Bush, AI, Sekler, IZinc in the physiology and pathology of the CNS. Nat Rev Neurosci 2009;10:780–791.CrossRefGoogle ScholarPubMed
Sham, PC, Curtis, DMonte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995;59:97–105.CrossRefGoogle ScholarPubMed
Shifman, S, Johannesson, M, Bronstein, M, Chen, SX, Collier, DA, Craddock, NJet al.Genome-wide association identifies a common variant in the reline gene that increases the risk of schizophrenia only in women. PLoS Genet 2008;4. e28 001–007.CrossRefGoogle Scholar
Sindreu, C, Palmiter, RD, Storm, DRZinc transporter ZnT–3 regulates presynaptic Erk 1/2 signalling and hippocampus–dependent memory. Proc Natl Acad Sci U S A 2011;108:3366–3370.CrossRefGoogle Scholar
Sindreu, CB, Varoqui, H, Erickson, JD, Pérez-Clausell, JBoutons containing vesicular zinc define a subpopulation of synapses with low AMPAR content in rat hippocampus. Cereb Cortex 2003;13:823–829.CrossRefGoogle ScholarPubMed
Wenzel, HJ, Cole, TB, Born, DE, Schwartzkroin, PA, Palmiter, RDUltrastructural localization of zinc transporter-3 (ZnT-3) to synaptic vesicle membranes within mossy fiber boutons in the hippocampus of mouse and monkey. Proc Natl Acad Sci U S A 1997;94:12676–12681.CrossRefGoogle ScholarPubMed
Williams, HJ, Norton, N, Dwyer, S, Moskvina, V, Nikolov, I, Carroll, LFine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Mol Psychiatry 2011;16:429–441.CrossRefGoogle ScholarPubMed
Zhang, F, Chen, Q, Ye, T, Lipska, BK, Straub, RE, Vakkalanka, Ret al.Evidence of sex-modulated association of ZNF804A with schizophrenia. Biol Psychiatry 2011;69:914–917.CrossRefGoogle ScholarPubMed
Supplementary material: File

Perez-Becerril et al. supplementary material

Supplementary materials

Download Perez-Becerril et al. supplementary material(File)
File 166.4 KB
Submit a response

Comments

No Comments have been published for this article.