Genetic Studies On Cognitive Function And Gene Polymorphism Of Type2Diabetes And Schizophrenia With Diabetes Patients

Diabetes mellitus is a metabolic disease that results from an interactionbetween genetic predispositions and environmental factors. The overallprevalence of detected diabetes mellitus in the general population in China isaround9.7%. T2DM accounts for85~90%of all diabetic cases. The patho-genesis of T2DM is characterized by a combination of impaired insulin ac-tivity through insulin resistance, and relative insulin deficiency through adysfunction of the pancreatic β-cell. and the incidence of mental disorders indiabetes patients is increasing, the common mental disorders were depression,anxiety, neurasthenia, and emotional instability.So the relationship betweendiabetes and psychiatry is being more and more attentioned.Schizophrenia is a complex genetic disorder and affects approximately1%of the population worldwide. Patients with schizophrenia appear to be atrisk of developing diabetes or impairment glucose tolerance, regardless ofwhether they are receiving antipsychotics treatment. The schizophrenia is con-sidered to be an independent risk factor of developing diabetes.Studies from the1950s onwards established that schizophrenia was posi-tively associated with type2diabetes. The prevalence of type2diabetes in pa-tients with schizophrenia was therefore found to be two to four times greaterthan that of general population. Genetic factors appear to take a part in the as-sociation between schizophrenia and diabetes. Many studies have reported thatup to50%of patients with schizophrenia have a familial history of type2dia-betes, compared with just4.6%of healthy adult controls.Some scholars believe that this phenomenon suggest that Multi-gene ge-netic diseases such as schizophrenia and type2diabetes may have somecommon genetic basis, Only due to different genetic background and differentenvironmental conditions led to different external phenotype in the two dis- eases. Mapping the genes by endophenotypes is one of the methods to find thecommon susceptible genes of schizophrenia and type2diabetes.BDNF is associated with insulin resistance and blood glucose dysfunc-tion in type2diabetes, and learning and memory of cognitive function inschizophrenia;insulin resistance and blood glucose dysfunction are both theheritable internal phenotype of type2diabetes, learning and memory is herita-ble internal phenotype of schizophrenia, so BDNF can be assumed to be theshared gene of the two diseases.Both of type2diabetes and schizophrenia patients have cognitive im-pairment.Cognitive impairment in patients with schizophrenia is involved inthe multiple domains, such as memory, attention, perception and processingspeed. Type2iabetes is a complex endocrine disease with series complica-tions and has been associated with cognitive deficits.Studies have found in-consistent results in regard to cognitive deficits in diabetes. However, ver-bal,memory and processing speed are the cognitive domains usually im-paired. As schizophrenia or diabetes alone has cognitive vulnerability, thetwo illnesses together may lead to an increased rate and magnitude of cogni-tive deficits. However, the contribution of diabetes to cognitive impairmentin schizophrenia has been seldom investigated. To our best knowledge, onlya recent study addressed the work in this field and found a preliminary resultthat schizophrenia with diabetes group had more cognitive impairment thanschizophrenia without diabetes group on the Western population.and it isworthy to reproduce this study in another non-Western culture such as usinga genetically more homogeneous Han Chinese inpatient population.In this study, we first compared the cognitive function in schizophreniawith diabetes, schizophrenia without diabetes, type2diabetes and healthycontrol group to see whether cognitive impairment is evident in the three pa-tients groups, and whether schizophrenia with diabetes patients has the worstcognitive impairment among these tested groups. We also test the BDNF levelin serum using Enzyme-Linked Immunosorbent Assay (ELISA) to see the re-lationship between serum BDNF level and cognitive function in the three pa- tients groups; Then, we studied the association between seven sin-gle-nucleotide polymorphisms of diabetes-related genes (MnSOD, FTO,BDNF) and type2diabetes as well as cognitive function in type2diabetes pa-tients,and the gene-gene interaction of seven SNPs in type2diabetes. Lastly,we studied whether BDNF gene is the shared gene of schizophrenia and type2diabetes. And we also studied the relationship between the BDNF polymor-phisms and type2diabetes in schizophrenia patients.Part-1Evidence of exacerbated cognitive deficits in schizophreniapatients with comorbid diabetesObjective: To compare the cognitive function in schizophrenia with dia-betes, schizophrenia without diabetes, type2diabetes and healthy controlgroup to see whether cognitive impairment is evident in schizophrenia withand without diabetes and diabetes only groups in comparison to healthy con-trols for the Chinese Han population, and whether schizophrenia with diabetespatients has the worst cognitive impairment among these tested groups, therelationship between serum BDNF level and cognitive function in the threepatients groups were also studied.Methods: There are four age-sex and education matched groups, includ-ing55schizophrenia with diabetes,127schizophrenia without diabetes,72type2diabetes and190healthy control groups,all the subjects were Hanpopulation of China. Diagnoses of type2diabetes were according to WHOdiagnostic criteria for type2diabetes in1999, and diagnoses of schizophreniawere made for each patient by two independent experienced psychiatrists andconfirmed by the Structured Clinical Interview for DSM-IV.Using RBANS toassess the cognitve function of all the subjects, using PANSS to assess theschizophrenia patients' psychopathology, the concentration of BDNF in serumwas tested using Enzyme-Linked Immunosorbent Assay (ELISA).Results:⑴The average level of fast glucose in schizophrenia with dia-betes (8.3±1.2mmol/l) and type2diabetes (9.5±2.3mmol/l) groups werehigher than healthy controls (5.1±0.7mmol/l)(P＜0.05). The average levelof triglyceride in schizophrenia with diabetes group (2.4±1.4mmol/l) was higher than healthy controls (1.7±1.1mmol/l)(P＜0.05).Compared to healthy controls, both schizophrenia with diabetes and type2diabetes groups showed significant increase in waist size (P＜0.05).Schizophrenia with and without diabetes groups had significant decrease inthe level of fast glucose and cholesterol as compared to type2diabetesgroup(P＜0.05).The triglyceride level was significantly higher in schizophre-nia with diabetes group than in schizophrenia without diabetes and type2dia-betes groups(P＜0.05). Schizophrenia with diabetes group also had higher fastglucose level than schizophrenia without diabetes group(P＜0.05).⑵Using Two-Way ANOVA,we found that type2diabetes had a interac-tion effect on immediate memory performance of schizophrenia pa-tients(Fdiabetes×schizophrenia=6.073,P=0.019),that is to say that type2diabetescan harden cognitive impairment in immediate memory of schizophrenia pa-tients.Overall, schizophrenia with and without diabetes and diabetes groupsperformed more poorly on several examined cognitive variables when com-pared to healthy controls. Schizophrenia with diabetes group obtained lowerperformance in all indexes of RBANS test when compared to healthy controlsexcept Visual/spatial performance (P＜0.05); Schizophrenia group obtainedlower performance in all indexes of RBANS test when compared to healthycontrols except Visual/spatial and attention performance (P＜0.05); type2diabetes group obtained lower performance in immediate and delayed memoryof RBANS test when compared to healthy controls (P＜0.05).Schizophrenia with diabetes group obtained lower immediate memoryperformance than schizophrenia without diabetes,type2diabetes and healthycontrol groups(P＜0.05). schizophrenia with diabetes group had lower totalRBANS score than schizophrenia without diabetes and healthy controls (P＜0.05), schizophrenia without diabetes had lower total RBANS score thanhealthy controls (P＜0.05).⑶Using Two-Way ANOVA,we found that type2diabetes had a interac-tion effect on serum BDNF level of schizophrenia patients(Fdiabe- tes×schizophrenia=111.481,P＜0.001),that is to say that type2diabetes had asynergies in serum BDNF level of schizophrenia patients.Serum BDNF level in schizophrenia with and without diabetes,type2diabetes groups were all lower than health control group(P＜0.05); SerumBDNF level in schizophrenia with diabetes group was lower than schizophre-nia without diabetes and type2diabetes groups (P＜0.05).⑷Serum BDNF level was associated with age and immediate memory inschizophrenia with diabetes group(P＜0.05); Serum BDNF level was associ-ated with PANSS negative symptom and immediate memory in schizophreniagroup(P＜0.05); Serum BDNF level was associated with fast blood glucoseand delayed memory in type2diabetes group(P＜0.05)。Conclusions:⑴Cognitive impairment was exsisted in all the three pa-tients groups, schizophrenia with diabetes patients had the worst cognitivefunction among the three patients groups, type2diabetes can harden cognitiveimpairment in immediate memory of schizophrenia patients;⑵Lipid metabo-lism disorders were exsisted in schizophrenia with diabetes group;⑶SerumBDNF level in the three patients groups were all lower than healthy controlgroup; Serum BDNF level in schizophrenia with diabetes group was lowerthan schizophrenia without diabetes and type2diabetes groups, type2diabe-tes had a synergies in serum BDNF level of schizophrenia patients;⑷SerumBDNF level was associated with age and immediate memory in schizophreniawith diabetes group; Serum BDNF level was associated with PANSS negativesymptom and immediate memory in schizophrenia group; Serum BDNF levelwas associated with fast blood glucose and delayed memory in type2diabetesgroup.Part-2Genetic association between seven single-nucleotide polymorphis-ms of diabetes-related genes (MnSOD, FTO, BDNF) and type2diabetesas well as cognitive function in type2diabetes patientsObjective: To explore the genetic association between seven sin-gle-nucleotide polymorphisms of diabetes-related genes (MnSOD, FTO,BDNF) and type2diabetes as well as cognitive function in type2diabetes pa- tients,and study the gene-gene interaction of seven SNPs in type2diabetes.Methods: There are two age-sex matched groups, including450type2diabetes and514healthy control groups, all the subjects were Han populationof China. Diagnoses of type2diabetes were according to WHO diagnosticcriteria for type2diabetes in1999.Using RBANS to assess the cognitve func-tion of all the subjects, seven single-nucleotide polymorphisms includingrs4880in MnSOD gene, rs6265, rs10835210, rs12273539, rs2030324inBDNF gene, rs9930506and rs9940128in FTO gene were detected usingPCR-RFLP teconology.Results:⑴Hardy-Weinberg equilibrium testThe chi-square (χ2)goodness-of-fit test showed that the genotype distri-butions of these7SNPs had no deviation from Hardy-Weinberg equilibriumboth in the patients group (P>0.05) and the control group (P>0.05).⑵Single locus analysisIn female samples, rs4880polymophism was associated with T2DM(OR=1.926,95%CI:1.310-2.830). In female samples, rs9930506polymo-phism was associated with T2DM (OR=1.464,95%CI:1.027-2.088). In fe-male samples, rs9940128polymophism was associated with T2DM(OR=1.828,95%CI:1.181-2.830). In the total samples (OR=1.4395,95%CI:1.093-1.894)and male samples(OR=1.629,95%CI:1.263-2.100), BDNF-rs6265polymophism was associated with T2DM (P＜0.05). As forrs2030324, rs12273539and rs10835210, their polymophisms were not asso-ciated with T2DM (P＞0.05);⑶gene-gene interaction analysisUsing MDR(Multifactor Dimensionality Reduction)(version1.1.0) toanalyze gene-gene interaction among the seven SNPs. The best model of twoSNPs is FTO-rs9930506and FTO-rs9940128(χ2=18.3405,P＜0.0001,CV=10/10, testing accuracy=0.7950),The best model of three SNPs isFTO-rs9930506, FTO-rs9940128and BDNF-rs6265(χ2=21.8518,P＜0.0001,CV=10/10, testing accuracy=0.8193).⑷Quantitative trait analysis The quantitative trait analysis was performed using the UNPHASEDprogram (version3.1.4). MnSOD-rs4880and BDNF-rs6265were both asso-ciated with delayded memory score in T2DM patients(χ2=6.213,P=0.024;χ2=5.572,P=0.049,respectly);MnSOD-rs4880was associated with thechanges of HOMA-IR, LDL-C and TC of T2DM patients(χ2=5.346,P=0.012;χ2=4.354,P=0.028;χ2=4.826,P=0.037); FTO-rs9930506was associated withthe change of BMI of T2DM patients(χ2=6.055,P=0.037); BDNF-rs6265,rs10835210,rs2030324were associated with the change of HDL-C of T2DMpatients(P＜0.05).Conclusions:⑴MnSOD-rs4880,FTO-rs9930506and FTO-rs9940128may be the susceptibility gene of female type2diabetes patients, andBDNF-rs6265may be the susceptibility gene of total and male diabetes pa-tients.⑵MnSOD-rs4880polymorphism was associated with the changes ofHOMA-IR, LDL-C and TC of T2DM patients,MnSOD-rs4880polymorphismmay take a part in type2diabetes through insulin resistence;andFTO-rs9930506was associated with the change of BMI of T2DM pa-tients,FTO-rs9930506may take a part in type2diabetes through obe-sity;BDNF-rs6265,rs10835210,rs2030324polymorphism were associated withthe change of HDL-C of T2DM patients.⑶MnSOD-rs4880,BDNF-rs6265polymorphism were associated withdelayed memory performance in type2diabetes patients.⑷FTO-rs9930506and FTO-rs9940128,BDNF-rs6265,FTO-rs9930506and FTO-rs9940128have gene-gene interactions in type2diabetes patients.Part-3Study on the comorbid gene between schizophrenia and type2diabetes and gene polymorphism of schizophrenia with diabetes patientsObjective: To explore whether BDNF was the comorbid gene betweenschizophrenia and type2diabetes, and whether BDNF-rs6265polymorphismwas playing a role in the development of diabetes in schizophrenia patients.Methods: There are four groups, including schizophrenia with diabetes,schizophrenia without diabetes, type2diabetes and healthy control groups, all the subjects were Han population of China. Diagnoses of type2diabetes wereaccording to WHO diagnostic criteria for type2diabetes in1999, and diagno-ses of schizophrenia were made for each patient by two independent experi-enced psychiatrists and confirmed by the Structured Clinical Interview forDSM-IV.Using RBANS to assess the cognitve function of all the subjects,BDNF-rs6265polymorphisms was detected by using PCR-RFLP teconology.Results:⑴Results of the comparison of schizophrenia patients andhealthy controls:BDNF-rs6265was not associated with schizophrenia (P＞0.05).BDNF-rs6265polymorphism associated with body mass index (BMI)and delayed memory performance of schizophrenia patients(χ2=4.435,P=0.035;χ2=6.138,P=0.015).⑵Results of the comparison of type2diabetes patients and healthycontrols were same to Part-2.⑶Results of the comparison of schizophrenia with diabetes andschizophrenia group: Age, education, family history of diabetes, BMI, fast-ing plasma glucose and triglycerides of schizophrenia group were higherthan that of schizophrenia with diabetes group (P＜0.05)；there was no sig-nificant difference in gender, clinical type, and type, dose adoption of drugsin the therapy between the two groups(P＞0.05). there was no significantdifference in concentration of total cholesterol, LDL, HDL and PANSS totalscores and sub-item scores(P＞0.05). BDNF-rs6265was not associated withT2DM in schizophrenia patients(P＞0.05),but genotype AG was the riskgenotype of T2DM in schizophrenia male patients.Conclusion:⑴BDNF-rs6265polymorphism was not associated withschizophrenia, but was associated with cognitive function and BMI in pa-tients with schizophrenia;⑵BDNF-rs6265may not be the shared gene of schizophrenia and type2diabetes;⑶BDNF-rs6265polymorphism was not associated with type2diabetesin schizophrenia patients, genotype AG was the risk genotype of T2DM inschizophrenia male patients.