Study On The SNP Of HTR3A And HTR3B With Susceptibility To Bipolar Disorder And Cognitive Impairment

Objectives Bipolar disorder (BPD) is a severe psychiatric disorder characterized by recurrent episodes of depression and mania or hypomania. Several studies analyzing genetic linkage and candidate genes, and genome-wide association studies have presented evidence of important genetic etiology in BPD. Serotonin imbalance may be one of the pathogenic mechanisms underlying BPD.Recent genetic association studies have highlighted the significance of serotonin receptors 3A and 3B in psychiatric conditions, such as schizophrenia,BPD,alcohol dependence, and depression. We attempted to explore the Tag SNP of HTR3A and HTR3B allele distribution and genotype in patients and normal controls by case-control study. In order to investigate the genetic susceptibility of HTR3A and HTR3B Tag SNP to BPD, also to further verify whether the phenotypic characteristics in bipolar disorder, cognitive impairment, provide an important reference for the theoretical research and clinical practice, and provide a theoretical basis for the early identification of BPD.Methods All of 21 Tag SNPs were genotyped in the study consisting of 209 bipolar disorder inpatients in Shandong Mental Health Center from June 2013 to May 2015 including 107 patients with bipolar I disorder and 102 patients with bipolar II disorder and 200 healthy individuals as control. Healthy control group was 200 cases during the same period. QIAamp mini whole blood DNA kit was used for 5ml EDTA anti-coagulation blood to extract DNA.All the tag SNPs were genotyped by Sequenom MassArray MALDI-TOF spectrometry. Plink 1.07, Haploview 4.2 and SPSS 20.0 softwares were used for the analysis of the genotypic and association haplotype to Bipolar disorder.The relationship between HTR3A and HTR3B polymorphism and the susceptibility to BPD in Chinese Han population was verified. For patients with bipolar disorder who met the criteria, the data were collected including family history, age of onset, frequency of onset and psychotic symptoms.In case group and healthy control group should complete MATRICS Consensus Cognitive Battery(including Trail Making Test A, The revised Hopkins Verbal Learning Test,Brief Assessment of Cognitition in Schizophrenia,The revised Brief Visuospatial Memory Test,Continuous performance Test,The mazes test and Mayer-Salovey-Caruso Emotional Intelligence Test etc.)within 1 week for association analysis of HTR3A and HTR3B Tag SNP with cognitive dysfunction of bipolar disorder.Results 1.The gene frequency of rs1062613, rs1176722,rs1176719, rs10160548, rs1176713 and rs1176746 had statistical significance (p<0.05) between case group and the control group. The genotype of rsl 176722, rs1176746 rs1176719, rs10160548 and rs1176713 had statistical significance (p<0.05) between case group and the control group. Also the number of patients with mutations was significantly higher than that of the wild type genotype (p<0.05).2.Sixteen Tag SNP of HTR3A and HTR3B successfully constructed 3 haplotype associated with bipolar disorder, with a linkage disequilibrium of 8 Tag SNPs in HTR3B in comparison of bipolar disorder and control group (p<0.05). A five Tag SNPs haplotype in HTR3A has a significant difference between bipolar I disorder and the control group (p<0.05), Four haplotypes were constructed between bipolar II disorder and the control group,which had no significant difference compared with the control group (p>0.05).3. The group carrying psychotic symptoms mutant gene of rs11604247, rs2276302, rs10160548 and rs1182457 was significantly increased (p<0.05) compared with wild homozygous individuals. While carrying the mutation gene of rs1062613 in individual spirit the disease symptoms was significantly reduced (p<0.05)compared with wild homozygous individuals. Nine SNP in HTR3B except rs1672717 and rs12795805 were significantly associated with psychotic symptoms of bipolar disorder. Individual with Six SNP gene mutation such as rs10789970, rs3831455, rs4938056, rsl2421126, rs1176746 and rs3782025 had more psychotic symptoms than wild homozygous individuals(p<0.05). Groups with mutant gene of rsl0160548,rs1176713,rs4938056, rs3782025 and rs1672717 were lower than the homozygous wild genotype group on average age of onset. Their average age of onset was early, with significant difference (p<0.05). Groups with mutant gene of rs1176746 were just reversed(p<0.05).The Groups with mutant gene of most SNP in HTR3A had longer duration of disease than homozygous wild genotype group, and the difference of rs1062613 and rs10789980 between the two groups was significant (p<0.05), while groups with mutant gene of most SNP in HTR3B were just reversed and the difference of rs1176744, rs2276305 and rs12795805 were significant(p<0.05). The SNP rs10789980 of HTR3A was positively correlated with the incidence of (r=0.283,p<0.01), and the SNP rs1062613 was positively correlated with family history (r=0.298, p<0.01). Eight SNP of HTR3B were significantly correlated with family history (r=0.262-0.424, p<0.01). Only rs2276305 was significantly correlated with the times of bipolar disorder (r=0.370,p<0.01).4. The difference of cognitive test T score between the three groups(bipolar I disorder, bipolar Ⅱ disorder and control group)was significant(F=4.525-8.539, p< 0.05). The cognitive test scores of bipolar disorder group were significantly reduced compared with the control. Bipolar II disorder group and control group had significant difference (p<0.05) in the four cognitive domain such as information processing speed, verbal learning, cognitive and social working memory and attention/vigilance. Cognitive test scores of mutant gene group with most of the SNP of HTR3 A is low, and the speed of information, processing and attention/vigilance domain score significantly decreased (p<0.05) comparing with the wild genotype group and the difference of SNP rs1176722, rs2276302 and rs1182457 of HTR3A were significantly (p<0.05). While cognitive test scores of mutant gene group of most of the HTR3B SNP were relatively high, especially in the information processing speed, working memory,attention/vigilance. Except for rs10789970, rs2276305 and rs1672717, cognitive test scores of mutant gene group of most of the HTR3B SNP were higher than wild genotype group(p<0.05).Conclusions 1.The mutant gene and genotype of rs1176722,rs1176719, rs10160548, rs1176713 of HTR3A and rs1176746 of HTR3B increased the risk of bipolar disorder. The mutant gene of rs1062613 in HTR3A may have a pathogenic role.2. There were linkage inheritance of five SNP in HTR3A in patients with bipolar I disorder and 8 SNP linkage inheritance in HTR3B in patients with bipolar disorder.3. HTR3B may be associated with psychotic symptoms in bipolar disorder patients. HTR3A may be related to the early onset of bipolar disorder in patients with bipolar disorder. Most of the site mutations in HTR3 A may be related to the extension of the duration of patients with bipolar disorder. The mutations in HTR3B may increase the risk of family inheritance. There was no close relationship between the SNP of HTR3A or HTR3B and bipolar disorder.4.The cognitive function of patients with bipolar disorder was lower than those of healthy controls. In patients with bipolar I disorder, cognitive impairment in the field of information processing speed, vocabulary learning, working memory and social cognition is relatively serious. HTR3A is associated with cognitive impairment in patients with bipolar disorder. HTR3B may have protective effect on cognitive function impairment in patients with bipolar disorder.5.The cognitive impairment of information processing speed, working memory and attention/vigilance could be seen as cognitive endophenotypes of bipolar disorder. Larger samples studies in Chinese were needed to verify our findings.