ABCB9 polymorphism rs61955196 is associated with schizophrenia in a Chinese Han population

BACKGROUND Schizophrenia (SCZ) is a complex disease which can be affected by both genetic and environmental factors. Prenatal famine exposure may cause changes in DNA methylation levels of genes. Meanwhile, maternal nutrition during pregnancy is a pivotal environmental factor in the development of SCZ. DNA methylation may be an intermediate factor mediating exposure to famine during pregnancy and SCZ, and DNA methylation quantitative trait loci might serve as a promising tool for linking SCZ and prenatal famine. AIM To analyze the association between prenatal famine exposure and SCZ risk in Northeast Han Chinese through analysis of DNA methylation related loci. METHODS A total of 954 Han Chinese from Northeast China were recruited, including 443 patients with SCZ and 511 healthy controls. The participants were further divided into famine (born in 1960-1962) and non-famine (born in 1963-1965) groups to investigate the effect of prenatal famine exposure. Four single-nucleotide polymorphisms (SNPs) selected according to the relevant literature were genotyped, namely, rs11917047 in PTPRG, rs2239681 in IGF2, rs3842756 in INSIGF, and rs61955196 in ABCB9. DNA were extracted from peripheral blood samples, and the genotypes of these SNP loci were detected using the improved Multiple Ligase Detection Reaction multiple SNP typing technique. The associations of the DNA methylation related SNPs with SCZ risk and prenatal famine, and their interactions were analyzed using logistic regression analysis and generalized multifactor dimensionality reduction (GMDR) software. RESULTS Based on the sequencing data, genotype distributions and allele frequencies of the four selected SNPs were determined. All genotype frequencies of the four SNPs in the healthy control group were tested for deviation from Hardy-Weinberg equilibrium (P > 0.05). Logistic regression analysis showed that rs61955196 was significantly associated with SCZ risk in the log-additive model [odds ratio (OR): 1.22; 95% confidence interval (CI): 1.01-1.48; P = 0.040]. We also found that the rs61955196 allele was related with an enhanced risk of SCZ (G>C, OR: 1.22; 95%CI: 1.01-1.47; P = 0.042). However, no associations were observed between rs11917047, rs2239681, or rs3842756 and SCZ risk. Under the optimal genetic model, no significant association of famine with the four SNPs was seen. Though the gene–gene interactions between rs2239681 and rs61955196 were found in GMDR analysis, none of the gene-gene interactions and gene-famine interactions were associated with the risk of SCZ. CONCLUSION Our study suggested that rs61955196 in ABCB9 is associated with SCZ susceptibility in Northeast Han Chinese, providing insight into genetic effects on SCZ.

[1]  B. Chiliza,et al.  DNA Methylation and Schizophrenia: Current Literature and Future Perspective , 2021, Cells.

[2]  R. Murray,et al.  DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia , 2021, eLife.

[3]  K. Scotlandi,et al.  The ABC subfamily A transporters: multifaceted players with incipient potentialities in cancer. , 2020, Seminars in cancer biology.

[4]  O. Howes,et al.  Schizophrenia-An Overview. , 2020, JAMA psychiatry.

[5]  S. Grieco,et al.  Insulin growth factor 2 (IGF2) as an emergent target in psychiatric and neurological disorders. Review , 2019, Neuroscience Research.

[6]  G. Davey Smith,et al.  Association of Maternal Neurodevelopmental Risk Alleles With Early-Life Exposures , 2019, JAMA psychiatry.

[7]  Y. Jiao,et al.  ATP binding cassette subfamily B member 9 (ABCB9) is a prognostic indicator of overall survival in ovarian cancer , 2019, Medicine.

[8]  James G. Scott,et al.  Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016 , 2018, Schizophrenia bulletin.

[9]  M. Falasca,et al.  ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward? , 2018, World journal of gastroenterology.

[10]  Xiaoying Zheng,et al.  Long-term effect of prenatal exposure to malnutrition on risk of schizophrenia in adulthood: Evidence from the Chinese famine of 1959–1961 , 2018, European Psychiatry.

[11]  Cuntong Wang,et al.  Schizophrenia in mid-adulthood after prenatal exposure to the Chinese Famine of 1959–1961 , 2017, Schizophrenia Research.

[12]  Eric E Schadt,et al.  Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression. , 2017, American journal of human genetics.

[13]  A. Cressant,et al.  Loss-of-function of PTPR γ and ζ, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice , 2017, Psychopharmacology.

[14]  Michael J. Ziller,et al.  The Future is The Past: Methylation QTLs in Schizophrenia , 2016, Genes.

[15]  Jin-hai Tang,et al.  Overexpression of microRNA-24 increases the sensitivity to paclitaxel in drug-resistant breast carcinoma cell lines via targeting ABCB9 , 2016, Oncology letters.

[16]  Robin M. Murray,et al.  An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation , 2016, Genome Biology.

[17]  Daniel R Weinberger,et al.  Association of DNA Methylation Differences With Schizophrenia in an Epigenome-Wide Association Study. , 2016, JAMA psychiatry.

[18]  Vince D. Calhoun,et al.  The association of DNA methylation and brain volume in healthy individuals and schizophrenia patients , 2015, Schizophrenia Research.

[19]  Tao Huang,et al.  Genetic differences among ethnic groups , 2015, BMC Genomics.

[20]  M. O’Donovan,et al.  Methylation quantitative trait loci in the developing brain and their enrichment in schizophrenia-associated genomic regions. , 2015 .

[21]  Daniel R Weinberger,et al.  Mapping DNA methylation across development, genotype, and schizophrenia in the human frontal cortex , 2015, Nature Neuroscience.

[22]  Jingde Zhu,et al.  Prenatal Nutritional Deficiency Reprogrammed Postnatal Gene Expression in Mammal Brains: Implications for Schizophrenia , 2015, The international journal of neuropsychopharmacology.

[23]  J. Ryan,et al.  Crucial timing in schizophrenia: role of DNA methylation in early neurodevelopment , 2014, Genome Biology.

[24]  D. Toncheva,et al.  Whole genome methylation analyses of schizophrenia patients before and after treatment , 2014, Biotechnology, biotechnological equipment.

[25]  K. Kasai,et al.  DNA methylation in schizophrenia: progress and challenges of epigenetic studies , 2012, Genome Medicine.

[26]  E. Susser,et al.  Prenatal nutrition, epigenetics and schizophrenia risk: can we test causal effects? , 2012, Epigenomics.

[27]  H. Putter,et al.  Prenatal Famine and Genetic Variation Are Independently and Additively Associated with DNA Methylation at Regulatory Loci within IGF2/H19 , 2012, PloS one.

[28]  T. Ekström,et al.  Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  P. Dominguez-Salas,et al.  Maternal nutritional status, C1 metabolism and offspring DNA methylation: a review of current evidence in human subjects , 2011, Proceedings of the Nutrition Society.

[30]  Lijun Cheng,et al.  Genetic control of individual differences in gene-specific methylation in human brain. , 2010, American journal of human genetics.

[31]  Pall I. Olason,et al.  Common variants conferring risk of schizophrenia , 2009, Nature.

[32]  J. Potash,et al.  Neuropsychiatric disorders: Shared genetics of bipolar disorder and schizophrenia , 2009, Nature Reviews Neurology.

[33]  Wei Wang,et al.  Famine, death, and madness: schizophrenia in early adulthood after prenatal exposure to the Chinese Great Leap Forward Famine. , 2009, Social science & medicine.

[34]  E. Susser,et al.  Prenatal nutritional deficiency and risk of adult schizophrenia. , 2008, Schizophrenia bulletin.

[35]  Ku Chee Seng,et al.  The success of the genome-wide association approach: a brief story of a long struggle , 2008, European Journal of Human Genetics.

[36]  R. Waterland.  Assessing the effects of high methionine intake on DNA methylation. , 2006, The Journal of nutrition.

[37]  P. Sham,et al.  Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. , 2005, JAMA.

[38]  A Rzhetsky,et al.  The human ATP-binding cassette (ABC) transporter superfamily. , 2001, Journal of lipid research.

[39]  E. Susser,et al.  Schizophrenia after prenatal exposure to the Dutch hunger winter of 1944–1945 , 1993, Schizophrenia Research.

[40]  B. Mowry,et al.  The emerging spectrum of allelic variation in schizophrenia: current evidence and strategies for the identification and functional characterization of common and rare variants , 2013, Molecular Psychiatry.