Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
BMC Psychiatry
Published in: BMC Psychiatry 1/2019

Open Access 01-12-2019 | Schizophrenia | Research article

SLC39A8 is a risk factor for schizophrenia in Uygur Chinese: a case-control study

Authors: Xuemin Jian, Jianhua Chen, Zhiqiang Li, Zhijian Song, Juan Zhou, Wei Xu, Yahui Liu, Jiawei Shen, Yonggang Wang, Qizhong Yi, Yongyong Shi

Published in: BMC Psychiatry | Issue 1/2019

Login to get access

Abstract

Background

Schizophrenia is a severe mental disease with high morbidity and heritability. The SLC39A8 gene is located in 4q24 and encodes a protein that transports many metal ions. Multiple previous studies found that one of the most pleiotropic single nucleotide polymorphisms (SNPs) in SLC39A8, rs13107325, is associated with schizophrenia in the European population. However, the polymorphism of this locus is rare in other populations. In China, the Han Chinese and the Uygur Chinese are two ethnic populations that originate from different races.

Methods

A case-control study was conducted with 983 schizophrenia cases and 1230 healthy controls of the Chinese Uygur population. To validate the most promising SNP, meta-analyses were conducted with the Han Chinese and the European PGC2 data sets reported previously.

Results

A susceptible locus, rs10014145 (pallele = 0.014, pallele = 0.098 after correction; pgenotype = 0.004, pgenotype = 0.032 after correction) was identified in case-control study of the Chinese Uygur population. Further, the association between rs10014145 and schizophrenia was supported by a meta-analysis of Han and Uygur Chinese samples (pooled OR [95% CI] =1.10 [1.03–1.17], Z = 2.73, p = 0.006). The association between rs10014145 and schizophrenia was not significant in a meta-analysis of combined Chinese and European samples (pooled OR [95% CI] =1.07 [1.00–1.14], Z = 1.88, and p = 0.06). In addition, the “CCAC” haplotype of rs4698844-rs233814-rs13114343-rs151394 was significantly associated with schizophrenia in Uygur Chinese (P = 0.003, corrected p = 0.012).

Conclusions

The results of this study support that SLC39A8 is a susceptible gene for schizophrenia in the populations of Han Chinese and Uygur Chinese in China, further studies are suggested to validate the association.
Appendix
Available only for authorised users
Literature
1.
Karam CS, Ballon JS, Bivens NM, Freyberg Z, Girgis RR, Lizardi-Ortiz JE, Markx S, Lieberman JA, Javitch JA. Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends Pharmacol Sci. 2010;31(8):381–90.CrossRef
2.
Burmeister M, McInnis MG, Zollner S. Psychiatric genetics: progress amid controversy. Nat Rev Genet. 2008;9(7):527–40.CrossRef
3.
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–23.CrossRef
4.
McCarthy S, Makarov V, Kirov G, Addington A, McClellan J, Yoon S, Perkins D, Dickel DE, Kusenda M, Krastoshevsky O, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009;41(11):1223–7.CrossRef
5.
O'Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V, Nikolov I, Hamshere M, Carroll L, Georgieva L, et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet. 2008;40(9):1053–5.CrossRef
6.
Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, Sklar P. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748–52.
7.
Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe'er I, Dudbridge F, Holmans PA, Whittemore AS, Mowry BJ, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009;460(7256):753–7.CrossRef
8.
Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, Werge T, Pietiläinen OPH, Mors O, Mortensen PB, et al. Common variants conferring risk of schizophrenia. Nature. 2009;460(7256):744–7.CrossRef
9.
Vacic V, McCarthy S, Malhotra D, Murray F, Chou H-H, Peoples A, Makarov V, Yoon S, Bhandari A, Corominas R, et al. Duplications of the neuropeptide receptor VIPR2 confer significant risk for schizophrenia. Nature. 2011;471(7339):499–503.CrossRef
10.
Shi Y, Li Z, Xu Q, Wang T, Li T, Shen J, Zhang F, Chen J, Zhou G, Ji W, et al. Common variants on 8p12 and 1q24.2 confer risk of schizophrenia. Nat Genet. 2011;43(12):1224–7.CrossRef
11.
Li Z, Chen J, Yu H, He L, Xu Y, Zhang D, Yi Q, Li C, Li X, Shen J, et al. Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia. Nat Genet. 2017;49:1576.CrossRef
12.
Yao Y-G, Kong Q-P, Wang C-Y, Zhu C-L, Zhang Y-P. Different matrilineal contributions to genetic structure of ethnic groups in the silk road region in China. Mol Biol Evol. 2004;21(12):2265–80.CrossRef
13.
Luo M, Zhou X, Ji H, Ma W, Liu G, Dai D, Li J, Chang L, Xu L, Jiang L, et al. Population difference in the associations of KLOTH promoter methylation with mild cognitive impairment in Xinjiang Uygur and Han populations. PLoS One. 2015;10(7):e0132156.CrossRef
14.
Zhao TM, Lee TD. Gm and km allotypes in 74 Chinese populations: a hypothesis of the origin of the Chinese nation. Hum Genet. 1989;83(2):101–10.CrossRef
15.
Waisberg M, Joseph P, Hale B, Beyersmann D. Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology. 2003;192(2–3):95–117.CrossRef
16.
Zalups RK, Ahmad S. Molecular handling of cadmium in transporting epithelia. Toxicol Appl Pharmacol. 2003;186(3):163–88.CrossRef
17.
Carrera N, Arrojo M, Sanjuán J, Ramos-Ríos R, Paz E, Suárez-Rama JJ, Páramo M, Agra S, Brenlla J, Martínez S, et al. Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia. Biol Psychiatry. 2012;71(2):169–77.CrossRef
18.
Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR. A global reference for human genetic variation. Nature. 2015;526(7571):68–74.CrossRef
19.
Schizophrenia Working Group of the Psychiatric Genomics C, Ripke S, Neale BM, Corvin A, JTR W, Farh K-H, Holmans PA, Lee P, Bulik-Sullivan B, Collier DA, et al. biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7.CrossRef
20.
Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, Smith AV, Tobin MD, Verwoert GC, Hwang SJ, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478(7367):103–9.CrossRef
21.
Wain LV, Verwoert GC, O'Reilly PF, Shi G, Johnson T, Johnson AD, Bochud M, Rice KM, Henneman P, Smith AV, et al. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet. 2011;43(10):1005–11.CrossRef
22.
Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Powell C, Vedantam S, Buchkovich ML, Yang J, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518(7538):197–206.CrossRef
23.
Li D, Achkar JP, Haritunians T, Jacobs JP, Hui KY, D'Amato M, Brand S, Radford-Smith G, Halfvarson J, Niess JH, et al. A pleiotropic missense variant in SLC39A8 is associated with Crohn's disease and human gut microbiome composition. Gastroenterology. 2016;151(4):724–32.CrossRef
24.
Ng E, Lind PM, Lindgren C, Ingelsson E, Mahajan A, Morris A, Lind L. Genome-wide association study of toxic metals and trace elements reveals novel associations. Hum Mol Genet. 2015;24(16):4739–45.CrossRef
25.
Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45(11):1274–83.CrossRef
26.
First MB, Spitzer RL, Gibbon M, JB W. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P). Biometrics Research. New York: State Psychiatric Institute; 2002.
27.
Li Z, Zhang Z, He Z, Tang W, Li T, Zeng Z, He L, Shi Y. A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://​analysis.​bio-x.​cn. Cell Res. 2009;19(4):519–23.CrossRef
28.
Shen J, Li Z, Chen J, Song Z, Zhou Z, Shi Y. SHEsisPlus, a toolset for genetic studies on polyploid species. Sci Rep. 2016;6:24095.CrossRef
29.
Faul F, Erdfelder E, Lang AG, Buchner A. G*power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39(2):175–91.CrossRef
30.
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.CrossRef
31.
Price AL, Helgason A, Palsson S, Stefansson H, St Clair D, Andreassen OA, Reich D, Kong A, Stefansson K. The impact of divergence time on the nature of population structure: an example from Iceland. PLoS Genet. 2009;5(6):e1000505.CrossRef
32.
Engelken J, Espadas G, Mancuso FM, Bonet N, Scherr AL, Jimenez-Alvarez V, Codina-Sola M, Medina-Stacey D, Spataro N, Stoneking M, et al. Signatures of evolutionary adaptation in quantitative trait loci influencing trace element homeostasis in liver. Mol Biol Evol. 2016;33(3):738–54.CrossRef
33.
Zhang C, Li J, Tian L, Lu D, Yuan K, Yuan Y, Xu S. Differential natural selection of human zinc transporter genes between African and non-African populations. Sci Rep. 2015;5:9658.CrossRef
34.
Li M, Wu D-D, Yao Y-G, Huo Y-X, Liu J-W, Su B, Chasman DI, Chu AY, Huang T, Qi L, et al. Recent positive selection drives the expansion of a schizophrenia risk nonsynonymous variant at SLC39A8 in Europeans. Schizophr Bull. 2016;42(1):178–90.PubMed
35.
Aschner M, Guilarte TR, Schneider JS, Zheng W. Manganese: recent advances in understanding its transport and neurotoxicity. Toxicol Appl Pharmacol. 2007;221(2):131–47.CrossRef
36.
Crichton RR, Dexter DT, Ward RJ. Brain iron metabolism and its perturbation in neurological diseases. J Neural Transm (Vienna, 1996). 2011;118(3):301–14.CrossRef
37.
Wright RO, Baccarelli A. Metals and neurotoxicology. J Nutr. 2007;137(12):2809–13.CrossRef
38.
Bitanihirwe BK, Cunningham MG: Zinc: the brain's dark horse. Synapse. 2009;63(11):1029–1049.CrossRef
39.
Nakashima AS, Dyck RH. Zinc and cortical plasticity. Brain Res Rev. 2009;59(2):347–73.CrossRef
40.
Dalton TP, He L, Wang B, Miller ML, Jin L, Stringer KF, Chang X, Baxter CS, Nebert DW. Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis. Proc Natl Acad Sci U S A. 2005;102(9):3401–6.CrossRef
41.
Marchetti C. Interaction of metal ions with neurotransmitter receptors and potential role in neurodiseases. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine. 2014;27(6):1097–113.CrossRef
42.
Zhang R, Witkowska K, Afonso Guerra-Assuncao J, Ren M, Ng FL, Mauro C, Tucker AT, Caulfield MJ, Ye S. A blood pressure-associated variant of the SLC39A8 gene influences cellular cadmium accumulation and toxicity. Hum Mol Genet. 2016;25(18):4117–26.CrossRef
43.
Rentschler G, Kippler M, Axmon A, Raqib R, Skerfving S, Vahter M, Broberg K. Cadmium concentrations in human blood and urine are associated with polymorphisms in zinc transporter genes. Metallomics : integrated biometal science. 2014;6(4):885–91.CrossRef
44.
Wu Y, Yao Y-G, Luo X-J. SZDB: a database for schizophrenia genetic research. Schizophr Bull. 2016;43(2):459–71.PubMedCentral
45.
Costas J. The highly pleiotropic gene SLC39A8 as an opportunity to gain insight into the molecular pathogenesis of schizophrenia. American journal of medical genetics Part B, Neuropsychiatric genetics. 2018;177(2):274–83.CrossRef
46.
Hess JL, Tylee DS, Barve R, de Jong S, Ophoff RA, Kumarasinghe N, Tooney P, Schall U, Gardiner E, Beveridge NJ, et al. Transcriptome-wide mega-analyses reveal joint dysregulation of immunologic genes and transcription regulators in brain and blood in schizophrenia. Schizophr Res. 2016;176(2–3):114–24.CrossRef
47.
Wockner LF, Noble EP, Lawford BR, Young RM, Morris CP, Whitehall VL, Voisey J. Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients. Transl Psychiatry. 2014;4:e339.CrossRef
48.
Baum AE, Hamshere M, Green E, Cichon S, Rietschel M, Noethen MM, Craddock N, McMahon FJ. Meta-analysis of two genome-wide association studies of bipolar disorder reveals important points of agreement. Mol Psychiatry. 2008;13(5):466–7.CrossRef
49.
Ollila HM, Soronen P, Silander K, Palo OM, Kieseppa T, Kaunisto MA, Lonnqvist J, Peltonen L, Partonen T, Paunio T. Findings from bipolar disorder genome-wide association studies replicate in a Finnish bipolar family-cohort. Mol Psychiatry. 2009;14(4):351–3.CrossRef
50.
Muglia P, Tozzi F, Galwey NW, Francks C, Upmanyu R, Kong XQ, Antoniades A, Domenici E, Perry J, Rothen S, et al. Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts. Mol Psychiatry. 2010;15(6):589–601.CrossRef
Metadata
Title
SLC39A8 is a risk factor for schizophrenia in Uygur Chinese: a case-control study
Authors
Xuemin Jian
Jianhua Chen
Zhiqiang Li
Zhijian Song
Juan Zhou
Wei Xu
Yahui Liu
Jiawei Shen
Yonggang Wang
Qizhong Yi
Yongyong Shi
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Schizophrenia
Published in
BMC Psychiatry / Issue 1/2019
Electronic ISSN: 1471-244X
DOI
https://doi.org/10.1186/s12888-019-2240-2

Other articles of this Issue 1/2019

BMC Psychiatry 1/2019 Go to the issue

Research article

Is depression a real risk factor for acute myocardial infarction mortality? A retrospective cohort study

Research article

Prevalence of prolonged grief disorder in a sample of female refugees

Research article

Using heart rate profiles during sleep as a biomarker of depression

Research article

Sociodemographic characteristics associated with adolescent depression in urban and rural areas of Hubei province: a cross-sectional analysis

Study protocol

The GET READY relapse prevention programme for anxiety and depression: a mixed-methods study protocol

Research article

Khat use and psychotic symptoms in a rural Khat growing population in Kenya: a household survey