Association Study Of CACNA1C And ITIHs Family Genes With Schizophrenia And Major Depressive Disorder In The Han Chinese Population

Mental diseases are caused by both genetic and environmental factors. The braindysfunction of patients leads to deficiency of cognitive, emotional, behavioral andother spiritual activities. Family, twin and adoption studies showed that genetic factorsplay a major role in the pathogenesis of schizophrenia and major depressive disorder.Using genetic association studies, researchers have found many susceptibility genes ofthese disorders. However, as these associations are sometimes inconsistent amongdifferent studies, the results of the association studies need to be validated amongdifferent populations.In the Caucasian population, CACNA1C and ITIH family genes were reported ascandidate genes of psychiatric disorders. However, the results have never beenvalidated in the Han Chinese population. Therefore, aiming to investigate whetherCACNA1C and ITIHs family gene confer risk to schizophrenia and major depressivedisorder, we carried out a large-scale genetic study in the Han Chinese population.Using Haploview software, TaqMan Genotyping technologies, Fludigm EP1platform, etc, we selected11SNP loci within CACNA1C genes and7tag SNP loci inITIHs family genes (ITIH1, ITIH3and ITIH4gene), and recruited1,235schizophrenia patients,1,045severe depression patients and1,235healthy controls forcase-control studies. Using bioinformatics methods, we further conductedprotein-protein interaction analysis on the CACNA1C and ITIHs family proteins andconducted a function enrichment analysis on the mutually interacted proteins. Theresults are as follows:(1) For CACNA1C gene, we found that rs1006737were significantly associatedboth with schizophrenia (Pallele=0.0014, Pgenotype=0.006, OR=1.384[95%CI=1.134~1.690]) and major depressive disorder (Pallele=0.0007, Pgenotype=0.003,OR=1.425[1.160~1.752]). After Bonferroni correction, we still found that rs1006737was significantly associated both with schizophrenia (Pallele=0.014) and majordepressive disorder (Pallele=0.007, Pgenotype=0.03). At the same time, we also found thatrs2239015, rs2283290and rs2239037were signifcantly associated withschizophrenia (rs2239015: Pallele=0.0003, Pgenotype=0.0015,OR=1.249[95%CI=1.100~1.400]; rs2283290: Pallele=0.039OR=1.181[95%CI=1.008~1.384]; rs2239037: Pallele=0.008, Pgenotype=0.016, OR=0.859[95%CI= 0.768~0.961]). After Bonferroni correction, we still found that rs2239015wasassociated with schizophrenia (Pallele=0.003, Pgenotype=0.015). After employing theassociation analysis which combines the schizophrenia and major depressive disordercases, we noticed that rs1006737and rs2239015were significantly associated withthe combined cases (rs1006737: Pallele=0.0002, Pgenotype=0.001, OR=1.403[1.174~1.677]; rs2239015: Pallele=0.001, Pgenotype=0.005, OR=1.249[1.100~1.400]).After Bonferroni correction, rs1006737and rs2239015were also significantlyassociated with the combined cases （rs1006737: Pallele=0.002, Pgenotype=0.01;rs2239015: Pallele=0.01).(2) For ITIHs family genes locus: ITIH1-ITIH3-ITIH4genes locus, we foundthat rs2710322, rs1042779, rs17331151and rs3821831showed statisticallysignificant association with schizophrenia before Bonferroni correction (rs2710322:Pallele=0.0003, Pgenotype=0.001, OR[95%CI]=1.278[1.117~1.462]; rs1042779:Pallele=0.008, Pgenotype=0.017, OR[95%CI]=1.164[1.040~1.303]; rs17331151:Pallele=0.015, OR[95%CI]=1.322[1.054~1.658]); rs3821831: Pgenotype=0.04,OR[95%CI]=1.044[0.866~1.258]). Rs2710322, rs1042779and rs3821831alsoshowed statistically significant association with major depressive disorder beforeBonferroni correction (rs2710322: Pallele=0.01, OR[95%CI]=0.840[0.735~0.959];rs1042779: Pallele=0.007, Pgenotype=0.012, OR[95%CI]=1.178[1.047~1.326];rs3821831: Pallele=0.0005, Pgenotype=0.001, OR[95%CI]=1.426[1.156~1.760]). AfterBonferroni correction, rs2710322was also associated with schizophrenia(Pallele=0.0018, Pgenotype=0.006) and rs3821831was associated with major depressivedisorder (Pallele=0.003, Pgenotype=0.006), while rs1042779was weakly associated withschizophrenia （Pallele=0.048）and major depressive disorder（Pallele=0.042）. Whenwe treat the schizophrenia and major depressive disorder as a combined case toanalyse, we found that rs1042779, rs17331151and rs3821831showed statisticallysignificant association with the combined case before Bonferroni correction(rs1042779: Palles=0.002, Pgenotype=0.003, OR[95%CI]=1.171[1.060~1.292];rs17331151: Pallele=0.029, OR[95%CI]=1.240[1.022~1.504]; rs3821831: Palle=0.038,Pgenotype=0.002, OR[95%CI]=1.193[1.010~1.410]). After Bonferroni correction, rs1042779and rs3821831were also significantly associated with the combined case(rs1042779: Palles=0.012, Pgenotype=0.018; rs3821831: Pgenotype=0.012)。（3）Using bioinformatics methods, we further conducted protein-proteininteraction analysis on the CACNA1C gene and ITIHs family genes：ITIH1, ITIH3,ITIH4which were proved to have significant association with both schizophreniaand major depressive disorder. Having constructed the protein-protein interactionnetwork, we conducted a function enrichment analysis on the mutually interactedproteins. We discovered that CACNA1C protein and ITIH3protein interacted in adirect manner while the three proteins of ITIHs family can form a protein-interactivenetwork directly or indirectly. The function enrichment analysis showed that:(a) theCACNA1C protein function which belongs to the functional field of ion transportingprotein was to be seen in the biologically process of calcium transportation, in theformation of cell calcium ion conjugates, in the calcium signaling, MAPK signalingand GnRH signaling;(b) ITIHs family protein function was to be seen in theprocesses of hyaluronic acid metabolism, mucoitin metabolism, glycosaminoglycanmetabolism, extracellular matrix formation, enzyme inhibitor activation, and thefunctional field of A type von willebrand factor etc. Among the functions, some ofthem have been verified to have close association with schizophrenia or majordepressive disorder.In summary, we first find that CACNA1C genes and ITIHs family genes wereassociated with schizophrenia and major depressive disorder in the Han Chinesepopulation. The finding will provide some valuable information for the diagnosis andtherapy of these diseases. Using bioinformatics analysis we found that CACNA1Cprotein and the ITIH3protein of ITIH family interacted in a direct way, the threeproteins of ITIHs family can form a protein interactive network either in a direct wayor indirect way. By function enrichment analysis, we made clear the enrichment scopeof the two, part of which have been verified to have close association withschizophrenia or major depressive disorder.Our results laid the foundation for biological research of mental illness andprovide experimental evidence for the Common Variants/Multiple Disease (CV/MD)hypothesis and it will be useful in influencing psychiatric research to move from reliance on a diagnostic and classification system that is based only on clinicaldescription towards a scheme that better reflects the underlying biology of thepsychiatric entities encountered in the clinics.