| The mechanism may be related to neuro-endoctine-immune system,which is involved in the complex interaction between mental disorders and somatic disease.This thesis focuses on the psychoneuroendocrinology related disorders,such as schizophrenia,major depressive disorders,primary dysmenorrhoea and Cushing's disease.Research strategies are carried out through the candidate gene,genome-wide association study or the whole exome sequencing study.Role played by the SP4 gene in schizophrenia and major depressive disorder in the han chinese populationPsychiatric disorders such as schizophrenia and major depressive disorder are likely to be caused by multiple susceptibility genes,each with small effects in increasing the risk of illness.Identifying DNA variants associated with schizophrenia and major depressive disorder is a crucial step in understanding the pathophysiology of these disorders.To investigate whether the SP4 gene plays a significant role in schizophrenia or major depressive disorder in the Han Chinese population.We focused on nine single nucleotide polymorphisms?SNPs?harbouring the SP4 gene and carried out case–control studies in 1,235 patients with schizophrenia,1,045 patients with major depressive disorder and 1,235 healthy controls recruited from the Han Chinese population.We found that rs40245 was significantly associated with schizophrenia in both allele and genotype distributions(Pallele = 5.00×10-4,Pallele = 4.00×10-3 after Bonferroni correction;Pgenotype = 2.30×10-3,Pgenotype = 0.018 after Bonferroni correction).The rs6461563 SNP was significantly associated with schizophrenia in the allele distributions(Pallele = 3.30×10-3,Pallele = 0.026 after Bonferroni correction).Our results suggest that common risk factors in the SP4 gene are associated with schizophrenia,although not with major depressive disorder,in the Han Chinese population.Genome-wide association study of schizophreniaTo further understand the genetic basis of susceptibility to schizophrenia,we conducted a genome-wide association study?GWAS?with replication in a total of 36,180 Chinese individuals?12,083 of whom are cases?and performed further transancestry meta-analyses with the most recent schizophrenia results from the Psychiatry Genomics Consortium?PGC2?.A significant excess in the directional consistency of schizophrenia risk alleles across ancestry groups was observed.Trans-ancestry metaanalyses,supported by polygenic scoring analysis,suggested that combining datasets from multiple ancestries is a valuable and powerful approach.Of the 117 genome-wide significant?GWS?index alleles?or their proxies?from 103 loci identified in the PGC2 study and available in our Chinese dataset,95%?109 at 98 loci?were overrepresented in Chinese cases,including 50%?58 at 56 loci?achieved nominal significance?P < 0.05?,and 75%?85 at 78 loci?continued to show GWS in the trans-ancestry analysis.The Chinese-only analysis identified seven GWS loci,three of these were also GWS in the trans-ancestry analyses which identified 109 GWS loci,yielding a total of 113 GWS loci in at least one of these analyses.Of the 113 risk loci,30 are novel,including four that were seen only in Chinese.We observed considerable improvements in the finemapping resolution at many susceptibility loci.Our results provide several lines of evidence supporting candidate genes at many loci and highlights some pathways?i.e.Glucagon-like Peptide-1 regulates insulin secretion pathway?for further research.We also observed a significant genetic correlation between schizophrenia and major depressive disorder in Chinese-ancestry subjects(rg = 0.43,P = 5.87×10-8).Together,our findings provide novel insight into the genetic architecture and biological etiology of schizophrenia.Genome-wide association study of primary dysmenorrhoea in Chinese populationPrimary dysmenorrhea,defined as painful menstrual cramps in the absence of pelvic pathology,is a common problem in women of reproductive age.Its etiology and pathophysiology remain largely unknown.Here we performed a two-stage genomewide association study and subsequent replication study to identify genetic factors associated with primary dysmenorrhea in total of 6,770 Chinese individuals.Our analysis provided evidence of a significant?P < 5×10–8?association at rs76518691 in the gene ZMIZ1 and at rs7523831 near NGF.ZMIZ1 has previously been associated with several autoimmune diseases,and NGF plays a key role in the generation of pain and hyperalgesia and has been associated with migraine.These findings provide future directions for research on susceptibility mechanisms for primary dysmenorrhea.Furthermore,our genetic architecture analysis provides molecular support for the heritability and polygenic nature of this condition.Genetic analysis of pathogenic genes in Cushing's diseaseCushing's disease results from corticotroph adenomas of the pituitary that hypersecrete adrenocorticotropin?ACTH?,leading to excess glucocorticoid and hypercortisolism.Mutations of the deubiquitinase gene USP8 occur in 35-62% of corticotroph adenomas.However,the major driver mutations in USP8 wild-type tumors remain elusive.Here,we identified recurrent mutations in the deubiquitinase gene USP48?predominantly encoding p.M415 I or p.M415V;21/91 subjects?and BRAF?encoding p.V600E;15/91 subjects?in corticotroph adenomas with wild-type USP8.Either USP48 or BRAF mutations are rarely detected in USP8 mutated cases?1/78 and 4/78,respectively?.In a total 169 cases,USP8,USP48 and BRAF mutations were significantly mutually exclusive.Our study thus contributes to the understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma and provides novel therapeutic targets for this disease. |
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