Genetics And Developmental Study Of Two Complacated Brain Disorders

Association between SLC39A8 and Schizophrenia in Uygur ChineseSchizophrenia is a severe mental disease with high morbidity and heritability.The genetic etiology of schizophrenia still needs more researches.The SLC39A8 gene locates in 4q24 and acts as many metal ions transmitters.Previously,multiple studies found rs 13107325,one of the most pleiotropic SNP in SLC39A8,to be associated with schizophrenia in European population.However,the polymorphism of this locus is rare in other populations.In order to investigate the genetic association between SLC39A8 and schizophrenia in other populations,we conducted a case-control study in 983 SCZ cases and 1218 healthy controls in the Chinese Uygur population and found rs10014145 to be significantly associated with schizophrenia(Pallele=0.016,Pallele=0.108 after Bonferroni correction;Pgenotype=0.005,Pgenotype=0.035 after Bonferroni correction).The association between rs10014145 and schizophrenia was supported by the meta-analysis of both Han and Uygur Chinese samples(pooled OR[950CI]=1.10[1.03-1.17],Z=2.71,and P=0.007).Additionally,the meta-analysis of Chinese and European samples showed significance too(pooled OR[95%CI]=1.03[1.01-1.06],Z=3.01,and P=0.003).In conclusion,our findings supported that rs10014145 of SLC39A8 is a susceptibility locus for human being for schizophrenia,and further studies should be performed to reveal the underlying mechanisms.Association analysis of Polymorphisms in FAN1 and Schizophrenia,Bipolar Disorder and Major Depressive Disorder in Han Chinese populationSchizophrenia(SCZ),bipolar disorder(BPD)and major depressive disorder(MDD)are three severe and major psychiatric disorders.Multiple susceptibility genes identified implicated in these disorders.FAN1,located in chromosome 15q13.3,is a component of Fanconi anemia pathway,specifically responsible for DNA interstrand cross-link repair.Studies have showed that are current copy number variant of FAN1 is associated with SCZ and BPD.To investigate the association between FAN1 and these three major mental disorders,we performed a case-control study in Han Chinese population.Three tag SNPs(rs4779794,rs7171212,rs4779796)of FAN1 were genotyped in 1248 SCZ cases,1344 BPD cases,1056 MDD cases and 1248 normal controls.We found that the genotype of rs7171212 was significantly associated with SCZ(Pgenotype=0.020,Pgenotype=0.030 after Bonferroni correction).Besides,the genotype of rs4779796 was also significantly associated with SCZ(Pgenotype=0.002,Pgenotype=0.005 after Bonferroni correction).Although the association between FAN1 and SCZ has been validated,the functional study will further be needed to validate the mechanism how FAN1 and even DNA damage repair pathway implicated in SCZ genesis.We can draw a conclusion that FAN1 is a susceptibility risk for schizophrenia.Functional study of USP48 and BRAF mutations in Cushing's diseaseCushing's disease originates from corticotroph adenomas of the pituitary charctered by adrenocorticotropin(ACTH)hyperseretion,resulting in excess hypercortisolism and glucocorticoid.Recently,deubiquitinase gene USP8 identified in 35-62%of corticotroph adenomas.However,the pathology of USP8 wild-type corticotroph adenomas remains unknown.Here we find recurrent mutations of deubiquitinase gene USP48(mainly encoding p.M415I/V;21 cases)and gene BRAF(encoding p.V600E;15 cases)in total of 91 corticotroph adenomas with wild-type USP8.Similar to USP8 mutants,both USP48 and BRAF mutants enhance the promoter activity and activate transcription of the gene encoding proopiomelanocortin(POMC),which is the precursor of ACTH.BRAFV600E activates POMC promoter via regulating MAPK pathway and increasing phosphorylation of Nur-77,c-Jun,c-Fos.USP48 mutants promote ACTH hyperseretion through NF-?B pathway.Moreover,primary corticotroph tumor cells harboring BRAFV600E are sensitive to the BRAF inhibitor vemurafenib.Our study contributes to the more understanding of the mechanism of the pathogenesis of this disease and provides new therapeutic targets for corticotroph adenoma with BRAFV600E.