Association Of H3F3B, NSD2, S1PR3, PRKCG, And GNA13 Genes With Schizophrenia In Chinese Han Population

Schizophrenia is a multifactorial and polygenic disease with a heritability of about 80%.Genetic factors are main factors,while environmental factors are incentives.The prevalence of schizophrenia is the highest among mental illness,which causes a huge burden for patients,families and even the society.There is growing evidence showing that schizophrenia is associated with epigenetic dysregulation.H3F3 B is a member of the Histone 3(H3)family.NSD2 as a methyltransferase is involved in the epigenetic modification of H3F3 B,specifically catalyzes the dimethylation of histone H3 lysine 36(H3K36).In addition,H3F3 B is located at 17q25.1,and NSD2 at 4p16.3.Both regions are susceptible region of schizophrenia.It has been confirmed that two genes are both neurodevelopmental genes and synaptic plasticity related genes.Abnormal synaptic plasticity is an important part in the neurodevelopmental disorder hypothesis of schizophrenia.As components of synaptic structures,sphingolipids are related to disturbances in neuronal plasticity,and they are involved in the structure and function of cell membranes in the brain.S1PR3,PRKCG and GNA13 are all members of the sphingolipid pathway,and they all affect synaptic plasticity which is crucial in the pathogenesis of SCZ.However,so far,there is no research showing that the interaction of these three genes is susceptible to SCZ.This study aimed to investigate the relationship between the polymorphisms of H3F3B(rs60700976,rs3214028),NSD2(rs13148597,rs75820801),S1PR3(rs6559331),GNA13(rs146686590,rs60016836),PRKCG(rs12460152,rs45548139,rs2242244)and the susceptibility to schizophrenia in Chinese population.A total of 810 schizophrenia patients and 490 healthy controls were recruited for genetic association analysis.In this study,we found that,there were significant differences in the genotype,allele,and haplotype distribution frequencies at the selected SNPs of H3F3B(rs3214028 and rs60700976)polymorphisms between the patients and controls(p<0.05).Moreover,our study showed that rs60700976 polymorphism was associated with the severity of symptoms,and G allele carriers might increase the severity of schizophrenia.Furthermore,the interaction between H3F3 B and NSD2 was associated to the susceptibility to schizophrenia.The best model was(H3F3B)rs60700976-(NSD2)rs75820801-(NSD2)rs13148597.The high-risk combination was rs13148597(CC)-rs60700976(GG)-rs75820801(TT)(OR=1.388[1.091-1.766],p=0.007).The low-risk combination was rs13148597(CC)-rs60700976(GG)-rs75820801(CT)(OR=0.57[0.330-0.985],p=0.042).The results of stratified analysis of three genes in sphingolipid pathway showed that the interaction of S1PR3(rs6559331)and PRKCG(rs2242244)was significantly associated with late-onset schizophrenia(OR=1.5509[0.4468-5.3835],P=0.036)after 1000 permutation tests.However,there was no significant difference in the genotype,allele,or haplotype distribution frequencies at the selected SNPs of GNA13,S1PR3,PRKCG polymorphisms between the patients and controls(p > 0.05).In conclusion,this study found that H3F3 B may be a susceptibility gene for schizophrenia.The interaction of NSD2 gene and H3F3 B gene is significantly associated with schizophrenia in Chinese Han population.In addition,S1PR3 and PRKCG genes are closely related to the susceptibility to late-onset schizophrenia.GNA13 gene may not be a susceptibility gene for schizophrenia in Chinese Han population.Our study reveals a potential genetic marker that may be used to predict the high-risk population,which helps to explain the genetic mechanism and provides a reference for the etiology of schizophrenia.