| 1 | 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数据与热解色谱、变异three loci (ITIH3/4, CACNA1C andSDCCAG8) 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, and identifies the first GWS evidence inschizophreniafor 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 betweenschizophreniaand bipolar disorder. |
| SCZ Keywords | schizophrenia |
| 2 | Neuron 2014 Aug 83: 805-22 |
| PMID | 25088364 |
| Title | SDCCAG8 regulates pericentriolar material recruitment and neuronal migration in the developing cortex. |
| Abstract | Mutations ofSDCCAG8are associated with nephronophthisis and Bardet-Biedl syndrome, as well asschizophrenia; however, the function ofSDCCAG8remains largely unknown. Here, we show thatSDCCAG8regulates centrosomal accumulation of pericentriolar material and neuronal polarization and migration in the developing mouse cortex.SDCCAG8expression is selectively elevated in newborn neurons prior to their commencement of radial locomotion, and suppression of this expression by short-hairpin RNAs or a loss-of-function allele impairs centrosomal recruitment of ?-tubulin and pericentrin, interferes with microtubule organization, decouples the centrosome and the nucleus, and disrupts neuronal migration. Moreover,SDCCAG8interacts and cotraffics with pericentriolar material 1 (PCM1), a centriolar satellite protein crucial for targeting proteins to the centrosome. Expression ofSDCCAG8carrying a human mutation causes neuronal migration defects. These results reveal a critical role forSDCCAG8in controlling centrosomal properties and function, and provide insights into the basis of neurological defects linked toSDCCAG8mutations. |
| SCZ Keywords | schizophrenia |
| 3 | Hum. Genet. 2015 Jan 134: 77-87 |
| PMID | 25284466 |
| Title | Refinement of schizophrenia GWAS loci using methylome-wide association data. |
| Abstract | Recent genome-wide association studies (GWAS) have made substantial progress in identifying disease loci. The next logical step is to design functional experiments to identify disease mechanisms. This step, however, is often hampered by the large size of loci identified in GWAS that is caused by linkage disequilibrium between SNPs. In this study, we demonstrate how integrating methylome-wide association study (MWAS) results with GWAS findings can narrow down the location for a subset of the putative casual sites. We use the diseaseschizophreniaas an example. To handle "data analytic" variation, we first combined our MWAS results with two GWAS meta-analyses (N�=�32,143 and 21,953), that had largely overlapping samples but different data analysis pipelines, separately. Permutation tests showed significant overlapping association signals between GWAS and MWAS findings. This significant overlap justified prioritizing loci based on the concordance principle. To further ensure that the methylation signal was not driven by chance, we successfully replicated the top three methylation findings near genesSDCCAG8, CREB1 and ATXN7 in an independent sample using targeted pyrosequencing. In contrast to the SNPs in the selected region, the methylation sites were largely uncorrelated explaining why the methylation signals implicated much smaller regions (median size 78�bp). The refined loci showed considerable enrichment of genomic elements of possible functional importance and suggested specific hypotheses aboutschizophreniaetiology. Several hypotheses involved possible variation in transcription factor-binding efficiencies. |
| SCZ Keywords | schizophrenia |
| 4 | PLoS ONE 2015 -1 10: e0133404 |
| PMID | 26193471 |
| Title | Network-Based Analysis of Schizophrenia Genome-Wide Association Data to Detect the Joint Functional Association Signals. |
| Abstract | schizophreniais a common psychiatric disorder with high heritability and complex genetic architecture. Genome-wide association studies (GWAS) have identified several significant loci associated withschizophrenia. However, the explained heritability is still low. Growing evidence has shownschizophrenia是由多个基因与温和的英孚吗fects. In-depth mining and integration of GWAS data is urgently expected to uncover disease-related gene combination patterns. Network-based analysis is a promising strategy to better interpret GWAS to identify disease-related network modules. We performed a network-based analysis on three independentschizophreniaGWASs by using a refined analysis framework, which included a more accurate gene P-value calculation, dynamic network module searching algorithm and detailed functional analysis for the obtained modules genes. The result generated 79 modules including 238 genes, which form a highly connected subnetwork with more statistical significance than expected by chance. The result validated several reported disease genes, such as MAD1L1, MCC,SDCCAG8, VAT1L, MAPK14, MYH9 and FXYD6, and also obtained several novel candidate genes and gene-gene interactions. Pathway enrichment analysis of the module genes suggested they were enriched in several neural and immune system related pathways/GO terms, such as neurotrophin signaling pathway, synaptosome, regulation of protein ubiquitination, and antigen processing and presentation. Further crosstalk analysis revealed these pathways/GO terms were cooperated with each other, and identified several important genes, which might play vital roles to connect these functions. Our network-based analysis ofschizophreniaGWASs will facilitate the understanding of genetic mechanisms ofschizophrenia. |
| SCZ Keywords | schizophrenia |