| 1 | Nat. Genet. 2011 Oct 43: 969-76 |
|---|---|
| PMID | 21926974 |
| Title | Genome-wide association study identifies five new schizophrenia loci. |
| Abstract | We examined the role of common genetic variation inschizophrenia在全基因组大小的一项全基因组关联研究中：欧洲血统的21,856个个人的发现样本和29,839个独立受试者的第2阶段复制样本。阶段1和2分析产生了全基因组的显着关联schizophreniafor seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 � 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four otherschizophrenia实现全基因组显着性的基因座包含miR137的预测靶标，表明miR137介导的失调是先前未知的病因机制schizophrenia。在与躁郁症样本（16,374个受影响个体和14,044个对照组）的联合分析中，三个基因座达到了全基因组的显着性：CACNA1C（rs4765905，p = 7.0°10（-9）），ANK3（ANK3）（-8））和ITIH3-ITIH4区域（RS2239547，p = 7.8�10（-9））。 |
| SCZ Keywords | schizophrenia |
| 2 | Nat. Genet. 2011 Oct 43: 977-83 |
| PMID | 21926972 |
| Title | Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. |
| Abstract | 我们进行了一项全基因组关联研究（GWAS），该研究是7,481个双相情感障碍（病例）和9,250个对照的人，作为精神病GWAS财团的一部分。我们的复制研究在4,496例双相情感障碍和42,422个独立对照中测试了34个SNP，发现34个SNP中有18个具有P <0.05，34个SNP中有31个具有相同效果方向的信号（P = 3.8-10（ - 10（ - 10（ - ））7））。对所有11,974例双相情感障碍病例和51,792个对照的分析证实了CACNA1C的基因组关联的重要证据，并确定了ODZ4中的新内含子变体。我们确定了一条途径，该途径由富含双相情感障碍关联间隔的钙通道的亚基组成。最后，对GWAS的组合分析schizophrenia和bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci. |
| SCZ Keywords | schizophrenia |
| 3 | Mol. Psychiatry 2013 Jun 18: 708-12 |
| PMID | 22614287 |
| Title | Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. |
| Abstract | TheschizophreniaPsychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association toschizophrenia。After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis ofschizophreniaattending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the newschizophrenia具有PGC的数据，三个基因座的变体（ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS inschizophreniaattained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated withschizophreniain the PGC. Our study independently confirms association to three loci previously reported to be GWS inschizophrenia，并确定第一个GWS证据schizophreniafor a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78-100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk betweenschizophrenia和bipolar disorder. |
| SCZ Keywords | schizophrenia |
| 4 | Front Neurosci 2014 -1 8: 331 |
| PMID | 25414627 |
| Title | Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders. |
| Abstract | 主要神经障碍高度heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders-attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), andschizophrenia（SCZ）。我们基于大规模的人类遗传研究策划了一份精心研究的基因清单，该研究基于已发表的全基因组关联研究（GWAS）的NHGRI目录。基于低但自由的GWAS P值（<10（-5）），总共接受了180个基因。22％的基因重叠两个或更多疾病。基因 - 共享子集最广泛的子集，包括六个疾病中的五个ANK3，AS3MT，CACNA1C，CACNB2，CACNB2，CNNM2，CSMD1，DPCR1，DPCR1，ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20-30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Our systematic comparative analysis of shared and unique genetic factors highlights key gene sets and molecular processes that may ultimately translate into improved diagnosis and treatment of these debilitating disorders. |
| SCZ Keywords | schizophrenia |
| 5 | J Affect Disord 2014 Jul 163: 110-4 |
| PMID | 24461634 |
| Title | Association analysis between suicidal behaviour and candidate genes of bipolar disorder and schizophrenia. |
| Abstract | The present study investigated associations between the strongest joint genetic risk variants for bipolar disorder (BD) andschizophrenia(SCZ) and a history of suicide attempt in patients with BD, SCZ and related psychiatric disorders. A history of suicide attempt was assessed in a sample of 1009 patients with BD, SCZ and related psychosis spectrum disorders, and associations with the joint genetic risk variants for BD and SCZ (rs2239547 (ITIH3/ 4-region) rs10994359 (ANK3)和rs4765905 (CACNA1C)) were investigated. Previously reported susceptibility loci for suicide attempt in BD were also investigated. Associations were tested by logistic regression with Bonferroni correction for multiple testing. The risk allele in rs2239547 (ITIH3/4-region) was significantly associated with a history of suicide attempt (p=0.01) after multiple testing correction (p threshold<0.017). The previous suicide attempt susceptibility loci were only nominally associated, but had the same direction of risk in the replication sample (sign test, p=0.02). Relatively small sample size and retrospective clinical assessment. We detected a novel association between suicide attempt and theITIH3BD，SCZ和相关精神病谱系障碍患者组合组合的 /4-区域。这对于理解严重精神疾病中自杀行为的分子机制可能很有用，尽管有必要复制。 |
| SCZ Keywords | schizophrenia |
| 6 | Int J Epidemiol 2014 Apr 43: 465-75 |
| PMID | 24618187 |
| Title | Recent challenges to the psychiatric diagnostic nosology: a focus on the genetics and genomics of neurodevelopmental disorders. |
| Abstract | Recent advances in the genetics of neurodevelopmental disorder (NDD) have demonstrated that rare mutations play a role not only in Mendelian syndromes, but in complex, common forms of NDDs as well. Strikingly, both common polymorphisms and rare variations in a single gene or genetic locus have been found to carry risk for conditions previously considered to be clinically and aetiologically distinct. Recent developments in the methods and tools available for studying complex NDDs have led to systematic and reliable genome-wide variant discovery. Both common as well as rare, and structural as well as sequence, genetic variations have been identified as contributing to NDDs. There are multiple examples in which the identical variant had been found to contribute to a wide range of formerly distinct diagnoses, including autism,schizophrenia, epilepsy, intellectual disability and language disorders. These include variations in chromosomal structure at 16p11.2, rare de novo point mutations at the gene SCN2A, and common single nucleotide polymorphisms (SNPs) mapping near loci encoding the genesITIH3, AS3MT, CACNA1C and CACNB2. These selected examples point to the challenges to current diagnostic approaches. Widely used categorical schema have been adequate to provide an entr� into molecular mechanisms of NDDs, but there is a need to develop an alternative, more biologically-relevant nosology. Thus recent advances in gene discovery in the area of NDDs are leading to a re-conceptualization of diagnostic boundaries. Findings suggest that epidemiological samples may provide important new insights into the genetics and diagnosis of NDDs and that other areas of medicine may provide useful models for developing a new diagnostic nosology, one that simultaneously integrates categorical diagnoses, biomarkers and dimensional variables. |
| SCZ Keywords | schizophrenia |
| 7 | Transl Psychiatry 2014 -1 4: e426 |
| PMID | 25136889 |
| Title | Investigation of manic and euthymic episodes identifies state- and trait-specific gene expression and STAB1 as a new candidate gene for bipolar disorder. |
| Abstract | 双相情感障碍（BD）是一种高度可遗传的精神病，其特征是躁狂和抑郁症的复发发作。为了识别新的BD基因和途径，本研究采用了三步方法。首先，在躁狂期和整个阶段都评估了BD患者的基因表达谱。这些曲线在个人内和对照组的基因表达谱进行了比较。其次，使用来自BD的精神病基因组学院全基因组关联研究（GWAS）的数据，对BD的潜在特征标记的那些差异表达的基因进行了验证。第三，使用途径分析方法研究了所暗示的分子机制。在目前的患者中，这种新颖的方法确定了：（i）一组差异表达的基因，特定于躁狂症和正肌症；（ii）两种情绪状态共有的一组差异表达的基因。在GWAS数据集成分析中，调整多次测试后，一个基因（Stab1）保持显着（p = 1.9°10（-4））。Stab1位于PBMR1和NEK4-ITIH1-附近ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD andschizophreniadata set. Pathway analyses in the mania versus control comparison revealed three distinct clusters of pathways tagging molecular mechanisms implicated in BD, for example, energy metabolism, inflammation and the ubiquitin proteasome system. The present findings suggest that STAB1 is a new and highly promising candidate gene in this region. The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD. |
| SCZ Keywords | schizophrenia |
| 8 | J Psychiatr Res 2014 Mar 50: 79-83 |
| PMID | 24373612 |
| Title | ITIH3多态性可能通过改变GLT8D1的表达水平来赋予对精神疾病的敏感性。 |
| Abstract | A recent genome-wide analysis indicated that a polymorphism (rs2535629) ofITIH3showed the strongest association signal with susceptibility to psychiatric disorders in Caucasian populations. The aim of the study was to replicate the association of rs2535629 withschizophrenia和major depressive disorder (MDD) in Japanese subjects. A total of 611 patients withschizophrenia，MDD的868和1193个健康对照成功地基因分型为RS2535629。在患者之间发现等位基因分布有显着差异schizophrenia和controls (odds ratio [OR]�=�1.21, 95% confidence interval [CI]: 1.05-1.39, P�=�0.0077). A similar trend was found for patients with MDD (OR�=�1.11, 95% CI: 0.98-1.26, P�=�0.092). The allele distribution in the combined patient group (schizophrenia和MDD）与对照组（或= �1.15，95％CI：1.03-1.28，p =�0.011）显着不同。39例MDD患者和40个健康对照组中全血样品的基因表达微阵列分析表明，RS2535629对ITIH4和GLT8D1的表达水平有很大影响。MDD患者的GLT8D1的表达水平明显高于对照组（P =�0.021）。据我们所知，本研究首次表明，在亚洲人群中，RS2535629与精神疾病的关联。我们的发现表明，RS2535629通过影响GLT8D1的表达水平来影响精神疾病的易感性。 |
| SCZ Keywords | schizophrenia |
| 9 | BR J Psychiatry 2015 12月207日：490-4 |
| PMID | 26206863 |
| Title | Loci with genome-wide associations with schizophrenia in the Han Chinese population. |
| Abstract | 一个大的schizophrenia全基因组关联研究（GWAS）和随后对欧洲血统个体的广泛复制研究确定了八个具有全基因组意义的新基因座，并表明miR137介导的途径在对倾向的倾向中起作用schizophrenia。 To validate the above findings in a Han Chinese population. We analysed the single nucleotide polymorphisms (SNPs) in the newly identifiedschizophreniacandidate loci and predicted MIR137 target genes based on our published Han Chinese populations (BIOX) GWAS data. We then analysed 18 SNPs from the candidate regions in an independent cohort that consisted of 3585 patients withschizophrenia和5496 controls of Han Chinese ancestry. We replicated the associations of five markers (P<0.05), including three that were located in the predicted MIR137 target genes. Two loci (ITIH3/4：rs2239547，p = 1.17�10（-10）和CALN1：rs2944829，p = 9.97�10（-9））在汉族人口中具有全基因组的重要性。 TheITIH3/4 locus has been reported to be of genome-wide significance in the European population. The successful replication of this finding in a different ethnic group provides stronger evidence for the association betweenschizophrenia和ITIH3/ 4。我们发现第一个genome-wide significant association ofschizophreniawith CALN1, which is a predicted target of MIR137, and thus provide new evidence for the associations between MIR137 targets andschizophrenia。 |
| SCZ Keywords | schizophrenia |