| 其他摘要 | Posttraumatic stress disorder (PTSD) is a clinically observable phenomenon that occurs following significant traumatic events, such as war, natural disasters, or other stressful events. Early twin and family studies indicate that PTSD is influenced by genetic factors. With the development of genotyping and genome sequencing technologies and the reduction in costs, research can now explore the genetic structure of PTSD susceptibility at the molecular level. Genetic variation refers to one or more genetic changes in an individual's DNA sequence, which make some individuals more susceptible to PTSD. Over the past decade, the literature on genetic variation in the field of PTSD has grown annually. However, due to substantial differences between studies in terms of design types, sample demographic variables, trauma types, diagnostic tools, etc., the high heterogeneity among studies, difficulties in reproducing and comparing results, hinder further exploration of the genetic structure of PTSD. Therefore, this study aims to comprehensively integrate current research in the field of PTSD genetics and further explore the data, attempting to identify the most reliable genes influencing PTSD, identify heterogeneity factors affecting results among different studies, and explain the biological mechanisms behind existing genetic results, ultimately visualizing the results.
Study 1 retrieved a total of 8,630 research records in the field of PTSD genetics through constructing search terms in the PubMed, Web of Science, psycINFO, and psycARTICLES databases, and included 266 articles after preliminary screening of abstracts. After statistical compilation, a total of 214 candidate gene association studies were identified, with the most studies conducted on Caucasian populations, with war as the trauma type, DSM-IV as the diagnostic tool, and young people as subjects; a total of 455 candidate genes were reported, and after counting the number of reports and the number of significant reports, SLC6A4, BDNF, FKBP5, COMT,
DRD2, CRHR1, SLC6A3, ADCYAP1R1, and OXTR were identified as the most promising candidate genes for PTSD. There were a total of 19 whole-genome association studies, with large-sample, high-quality whole-genome association studies being the trend in recent years, but the populations involved in current whole-genome association studies only include Caucasian, African, and Latino populations.
Study 2 conducted meta-analyses on candidate gene association studies, analyzed tissue-specific differential expression and pathway enrichment of candidate genes reported in two or more studies, and analyzed tissue-specific differential expression and pathway enrichment of at least once significantly reported candidate genes. The results updated the meta-analyses of six genes, SLC6A4, SLC6A3, COMT, FKBP5,
OXTR, and NR3C1, and found significant associations only between SLC6A3 and
FKBP5 and PTSD diagnosis. Subgroup analysis showed that SLC6A4 was significantly associated with PTSD in control groups without trauma exposure and in studies with war trauma types, but not in other cases; SLC6A3 was significantly associated with PTSD in studies with young people as subjects and mixed trauma types, but not in other age groups or trauma types; FKBP5 showed different associations with PTSD in studies with different ancestries, different age groups of subjects, and different trauma types. Differential expression analysis showed that the PTSD candidate gene set exhibited a specific expression pattern in brain tissues, with significant downregulation in prostate, testis, and breast tissues; pathway enrichment analysis showed that the PTSD candidate gene set is involved in many biological processes, with the most significant being the interaction between neuroactive ligands and receptors, neurotransmitter receptor activity, postsynaptic membrane cellular components, response to ethanol, and chemical synaptic signaling processes.
Study 3 conducted integrated analysis of data from whole-genome association studies and tissue-specific differential expression analysis and pathway enrichment analysis of genes that reached the suggested significance threshold. The integrated analysis did not identify new significant genes, and differential expression analysis and pathway enrichment analysis did not reveal significant results either. Enrichment analysis of merged candidate and whole-genome association gene sets revealed four new pathways: catecholamine uptake, vitamin D sensitive calcium signaling in depression, phosphodiesterases in neuronal function and regulation of G protein coupled receptor signaling pathway.
Study 4 visualized the statistical analysis results of the entire study through a website, established a relational database with structured data through MySQL. The relational database and the statistical analysis results were displayed on the constructed PTSD genetics website, PTSDgenetics.
In summary, this study conducted comprehensive data integration and mining in the field of PTSD genetics. Currently, candidate gene association studies are the primary research method in this field, playing an important role and providing significant results. Large-sample, high-quality whole-genome association studies are the future trend. SLC6A3 and FKBP5 are the most reliable candidate associated genes for PTSD. Age group, trauma type, and ancestral component are the main heterogeneity factors affecting the results of PTSD genetics research, and the signaling process between neurotransmitters is the most likely biological mechanism involved in PTSD etiology. Future studies should increase large-sample whole genome association studies, study the genetic mechanisms of PTSD from different sample characteristics and different trauma type classifications, and verify the influence of the neurotransmitter system on PTSD from multiple perspectives, providing new insights for the diagnosis, prevention, and clinical treatment of PTSD. |
修改评论