Top

BMC Psychiatry

Published in:

Open Access 01-12-2021 | Schizophrenia | Research

Association study between genetic variants and the risk of schizophrenia in the Chinese population based on GWAS-implicated 6p21.3–23.1 human genome region: a case-control study

Authors: Gangqin Li, Jie Dai, Hao Liu, Yushan Lin, Qiaoni Liu, Kaiyuan Zheng, Suyu Li, Siyu Chen, Yi Ye

Published in: BMC Psychiatry | Issue 1/2021

Abstract

Background

Schizophrenia is a polygenic disease; however, the specific risk genetic variants of schizophrenia are still largely unknown. Single nucleotide polymorphism (SNP) is important genetic factor for the susceptibility of schizophrenia. Investigating individual candidate gene contributing to disease risk remains important.

Methods

In a case-control study, five SNPs located in 6p21.3-p23.1 including rs2021722 in human leukocyte antigen (HLA) locus and rs107822, rs383711, rs439205 and rs421446 within the upstream of microRNA-219a-1 were genotyped in 454 schizophrenia patients and 445 healthy controls to investigate the possible association between the loci and schizophrenia in a Han Chinese population.

Results

Our results showed significant associations between the rs2021722 and schizophrenia in allele (A vs. G: adjusted OR = 1.661, 95%CI = 1.196–2.308), co-dominant (AG vs. GG: OR = 1.760, 95%CI = 1.234–2.510) and dominant genetic model (AG + AA vs. GG: OR = 1.756, 95%CI = 1.237–2.492), respectively. Haplotype analysis showed that TGGT and CAAC were protective factor for schizophrenia compared with TAAC haplotype (OR = 0.324, 95% CI = 0.157–0.672; OR = 0.423, 95% CI = 0.199–0.900).

Conclusions

These findings indicate that rs2021722 in HLA locus might be involved in pathogenesis of schizophrenia and that genotypes AG and allele A of the locus are risk factors for schizophrenia in the Han Chinese population, confirming the association between immune system and schizophrenia.

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789–858.CrossRef

Yan X, Zhao X, Li J, He L, Xu M. Effects of early-life malnutrition on neurodevelopment and neuropsychiatric disorders and the potential mechanisms. Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;20(83):64–75. https://doi.org/10.1016/j.pnpbp.2017.12.016.CrossRef

Chen J, Zhao X, Cui L, He G, Wang X, Wang F, et al. Genetic regulatory subnetworks and key regulating genes in rat hippocampus perturbed by prenatal malnutrition: implications for major brain disorders. Aging (Albany NY). 2020;12(9):8434–58. https://doi.org/10.18632/aging.103150.CrossRef

Wang X, Jiao X, Tian Y, Zhang J, Zhang Y, Li J, et al. Shanghai birth cohort study. Associations between maternal vitamin D status during three trimesters and cord blood 25(OH) D concentrations in newborns: a prospective Shanghai birth cohort study. Eur J Nutr. 2021;60(6):3473–83. https://doi.org/10.1007/s00394-021-02528-w.CrossRefPubMed

Jv O, Kapur S. Schizophrenia. Lancet. 2009;374(9690):635–45. https://doi.org/10.1016/S0140-6736(09)60995-8.CrossRef

Wu Y, Cao H, Baranova A, Huang H, Li S, Cai L, et al. Multi-trait analysis for genome-wide association study of five psychiatric disorders. Transl Psychiatry. 2020;10(1):209. https://doi.org/10.1038/s41398-020-00902-6.CrossRefPubMedPubMedCentral

Schizophrenia Psychiatric Genome-Wide Association Study Consorttium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43(10):969–76. https://doi.org/10.1038/ng.940.CrossRef

Aberg KA, Liu Y, Bukszar J, McClay JL, Khachane AN, Andreassen OA, et al. A comprehensive family-based replication study of schizophrenia genes. JAMA Psychiatry. 2013;70(6):573–81. https://doi.org/10.1001/jamapsychiatry.2013.288.CrossRefPubMedPubMedCentral

Li H, Wang X, Lu X, Zhu H, Li S, Duan S, et al. Co-expression network analysis identified hub genes critical to triglyceride and free fatty acid metabolism as key regulators of age-related vascular dysfunction in mice. Aging (Albany NY). 2019;11(18):7620–38. https://doi.org/10.18632/aging.102275.CrossRef

10.

Geaghan M, Cairns MJ. Small RNA dysregulation in neurocognitive and neuropsychiatric disorders. In: Geaghan M, Cairns MJ, editors. Small RNA dysregulation in neurocognitive and neuropsychiatric disorders. Cambridge: Academic Press; 2017.CrossRef

11.

Cao T, Zhen XC. Dysregulation of miRNA and its potential therapeutic application in schizophrenia. CNS Neurosci Ther. 2018;24(7):586–97. https://doi.org/10.1111/cns.12840.CrossRefPubMedPubMedCentral

12.

Hunsberger JG, Austin DR, Chen G, Manji HK. MicroRNAs in mental health: from biological underpinnings to potential therapies. NeuroMolecular Med. 2009;11(3):173–82. https://doi.org/10.1007/s12017-009-8070-5.CrossRefPubMedPubMedCentral

13.

Bravo JA, Dinan TG. MicroRNAs: a novel therapeutic target for schizophrenia. Curr Pharm Des. 2011;17(2):176–88. https://doi.org/10.2174/138161211795049543.CrossRefPubMed

14.

Kocerha J, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caon MG, et al. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. PNAS. 2009;106(9):3507–12. https://doi.org/10.1073/pnas.0805854106.CrossRefPubMedPubMedCentral

15.

Zhang Y, Fan M, Wang Q, He G, Fu Y, Li H, et al. Polymorphisms in microRNA genes and genes involving in NMDAR signaling and schizophrenia: a case-control study in Han Chinese population. Sci Rep. 2015;5(1):12984. https://doi.org/10.1038/srep12984.CrossRefPubMedPubMedCentral

16.

Kantrowitz JT, Javitt DC. N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull. 2010;83(3–4):108–21. https://doi.org/10.1016/j.brainresbull.2010.04.006.CrossRefPubMedPubMedCentral

17.

Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common variants conferring risk of schizophrenia. Nature. 2009;460(7256):744–7. https://doi.org/10.1038/nature08186.CrossRefPubMedPubMedCentral

18.

Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe'er I, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009;460(7256):753–7. https://doi.org/10.1038/nature08192.CrossRefPubMedPubMedCentral

19.

McAllister AK, van de Water J. Breaking boundaries in neural-immune interactions. Neuron. 2009;64(1):9–12. https://doi.org/10.1016/j.neuron.2009.09.038.CrossRefPubMedPubMedCentral

20.

Kipnis J. Multifaceted interactions between adaptive immunity and the central nervous system. Science. 2016;353(6301):766–71. https://doi.org/10.1126/science.aag2638.CrossRefPubMedPubMedCentral

21.

Muller N, Riedel M, Gruber R, Ackenheil M, Schwarz MJ. The immune system and schizophrenia. An integrative view. Ann N Y Acad Sci. 2000;917:456–67. https://doi.org/10.1111/j.1749-6632.2000.tb05410.x.CrossRefPubMed

22.

Miuller N, Schwarz MJ. The immunological basis of glutamatergic disturbance in schizophrenia: towards an integrated view. J Neural Transm Suppl. 2007;72:269–80. https://doi.org/10.1007/978-3-211-73574-9_33.CrossRef

23.

Zheng S, Zhao T, Yuan S, Yang L, Ding J, Cui L, et al. Immunodeficiency promotes adaptive alterations of host gut microbiome: An observational metagenomic study in mice. Front Microbiol. 2019;10:2415. https://doi.org/10.3389/fmicb.2019.02415.CrossRefPubMedPubMedCentral

24.

Upthegrove R, Manzanares-Teson N, Barnes NM. Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophr Res. 2014;155(1–3):101–8. https://doi.org/10.1016/j.schres.2014.03.005.CrossRefPubMed

25.

Shatz CJ. MHC class I: An unexpected role in neuronal plasticity. Neuron. 2009;64(1):40–5. https://doi.org/10.1016/j.neuron.2009.09.044.CrossRefPubMedPubMedCentral

26.

Glynn MW, Elmer BM, Garay PA, Liu XB, Needleman LA, El-Sabeawy F, et al. MHCI negatively regulates synapse density during the establishment of cortical connections. Nat Neurosci. 2011;14(4):442–51. https://doi.org/10.1038/nn.2764.CrossRefPubMedPubMedCentral

27.

Goddard CA, Butts DA, Shatz CJ. Regulation of CNS synapses by neuronal MHC class I. Proc Natl Acad Sci U S A. 2007;104(16):6828–33. https://doi.org/10.1073/pnas.0702023104.CrossRefPubMedPubMedCentral

28.

Balu DT, Coyle JT. Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci Biobehav Rev. 2011;35(3):848–70. https://doi.org/10.1016/j.neubiorev.2010.10.005.CrossRefPubMed

29.

Stephan KE, Baldeweg T, Friston KJ. Synaptic plasticity and dysconnection in schizophrenia. Biol Psychiatry. 2006;59(10):929–39. https://doi.org/10.1016/j.biopsych.2005.10.005.CrossRefPubMed

30.

Allen AJ, Griss ME, Folley BS, Hawkins KA, Pearlson GD. Endophenotypes in schizophrenia: a selective review. Schizophr Res. 2009;109(1–3):24–37. https://doi.org/10.1016/j.schres.2009.01.016.CrossRefPubMedPubMedCentral

31.

Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ. Functional requirement for class I MHC in CNS development and plasticity. Science. 2000;290(5499):2155–9. https://doi.org/10.1126/science.290.5499.2155.CrossRefPubMedPubMedCentral

32.

Tao B, Xiao Y, Hu N, Shah C, Liu L, Gao X, et al. Reduced cortical thickness related to single nucleotide polymorphisms in the major histocompatibility complex region in antipsychotic-naive schizophrenia. Brain Behav. 2019;9(5):e01253. https://doi.org/10.1002/brb3.1253.CrossRefPubMedPubMedCentral

33.

Cheng HY, Papp JW, Varlamova O, Dziema H, Russell B, Curfman JP, et al. microRNA modulation of circadian-clock period and entrainment. Neuron. 2007;54(5):813–29. https://doi.org/10.1016/j.neuron.2007.05.017.CrossRefPubMedPubMedCentral

34.

Zhou X, Li Q, Xu J, Zhang X, Zhang H, Xiang Y, et al. The aberrantly expressed miR-193b-3p contributes to preeclampsia through regulating transforming growth factor-β signaling. Sci Rep. 2016;6(1):19910. https://doi.org/10.1038/srep19910.CrossRefPubMedPubMedCentral

35.

Jin G, Xu M, Zou M, Duan S. The processing, gene regulation, biological functions, and clinical relevance of N4-Acetylcytidine on RNA: a systematic review. Mol Ther Nucleic Acids. 2020;20:13–24. https://doi.org/10.1016/j.omtn.2020.01.037.CrossRefPubMedPubMedCentral

36.

Lyu L, Yao J, Wang M, Zheng Y, Xu P, Wang S, et al. Overexpressed pseudogene HLA-DPB2 promotes tumor immune infiltrates by regulating HLA-DPB1 and iindicates a better prognosis in breast cancer. Front Oncol. 2020;10:1245. https://doi.org/10.3389/fonc.2020.01245.CrossRefPubMedPubMedCentral

37.

Sun YJ, Yu Y, Zhu GC, Sun ZH, Xu J, Cao JH, et al. Association between single nucleotide polymorphisms in MiR219-1 and MiR137 and susceptibility to schizophrenia in a Chinese population. FEBS Open Bio. 2015;5(1):774–8. https://doi.org/10.1016/j.fob.2015.08.008.CrossRefPubMedPubMedCentral

38.

Jiang L, Wang K, Lo K, Zhong Y, Yang A, Fang X, et al. Sex-specific association of circulating ferritin level and risk of type 2 diabetes: a dose-response meta-analysis of prospective studies. J Clin Endocrinol Metab. 2019;104(10):4539–51. https://doi.org/10.1210/jc.2019-00495.CrossRefPubMed

39.

Smrt RD, Szulwach KE, Pfeiffer RL, Li X, Guo W, Pathania M, et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells. 2010;28(6):1060–70. https://doi.org/10.1002/stem.431.CrossRefPubMedPubMedCentral

40.

Hatakeyama S. TRIM family proteins: roles in autophagy, immunity, and carcinogenesis. Trends Biochem Sci. 2017;42(4):297–311. https://doi.org/10.1016/j.tibs.2017.01.002.CrossRefPubMed

41.

Zhang FQ, Rao SQ, Cao HB, Zhang ZR, Wang Q, Xu Y, et al. Genetic evidence suggests posttraumatic stress disorder as a subtype of major depressive disorder. J Clin Investig. 2021;27:145942. https://doi.org/10.1172/JCI145942 Epub ahead of print.CrossRef

42.

Wang XH, Fang XX, Zheng WR, Zhou JH, Song ZJ, Xu MQ, et al. Genetic support of a causal relationship between iron status and type 2 diabetes: a Mendelian randomization study. J Clin Endocrinol Metab. 2021:dgab454. https://doi.org/10.1210/clinem/dgab454.

43.

Zhang FQ, Baranova A, Zhou C, Cao HB, Chen J, Zhang XR, et al. Causal influences of neuroticism on mental health and cardiovascular disease. Hum Genet. 2021;140(9):1267–81. https://doi.org/10.1007/s00439-021-02288-x.CrossRefPubMed

44.

Yu H, Pan R, Qi Y, Zheng Z, Li J, Li H, et al. LEPR hypomethylation is significantly associated with gastric cancer in males. Exp Mol Pathol. 2020;116:104493. https://doi.org/10.1016/j.yexmp.2020.104493.CrossRefPubMed

45.

Liu M, Li F, Yan H, Wang K, Ma Y, Alzheimer’s Disease Neuroimaging Initiative, et al. A multi-model deep convolutional neural network for automatic hippocampus segmentation and classification in Alzheimer’s disease. Neuroimage. 2020;208:116459. https://doi.org/10.1016/j.neuroimage.2019.116459.CrossRefPubMed

Title: Association study between genetic variants and the risk of schizophrenia in the Chinese population based on GWAS-implicated 6p21.3–23.1 human genome region: a case-control study
Authors: Gangqin Li
Jie Dai
Hao Liu
Yushan Lin
Qiaoni Liu
Kaiyuan Zheng
Suyu Li
Siyu Chen
Yi Ye
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Schizophrenia
Published in: BMC Psychiatry / Issue 1/2021
Electronic ISSN: 1471-244X
DOI: https://doi.org/10.1186/s12888-021-03496-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Association study between genetic variants and the risk of schizophrenia in the Chinese population based on GWAS-implicated 6p21.3–23.1 human genome region: a case-control study

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Risk factors, physical and mental health burden of male and female pathological gamblers in the German general population aged 40–80

Epilepsy and other seizure disorders in acute psychiatric inpatients

One year follow-up and mediation in cognitive behavioral therapy and acceptance and commitment therapy for adult depression

Mental health screening amongst police officers: factors associated with under-reporting of symptoms

Effects of sources of social support and resilience on the mental health of different age groups during the COVID-19 pandemic

Investigating defensive functioning and alexithymia in substance use disorder patients