| 1 | Eur. J. Hum. Genet. 2012 Sep 20: 1004-8 |
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| PMID | 22433715 |
| Title | Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes. |
| Abstract | There is genetic evidence thatschizophreniais a polygenic disorder with a large number of loci of small effect on disease susceptibility. Genome-wide association studies (GWASs) ofschizophreniahave had limited success, with the best finding at the MHC locus at chromosome 6p. A recent effort of the Psychiatric GWAS consortium (PGC) yielded five novel loci forschizophrenia. In this study, we aim to highlight additionalschizophreniasusceptibility loci from the PGC study by combining the top association findings from the discovery stage (9394schizophreniacases and 12?462 controls) with expression QTLs (eQTLs) and differential gene expression in whole blood ofschizophreniapatients and controls. We examined the 6192 single-nucleotide polymorphisms (SNPs) with significance threshold at P<0.001. eQTLs were calculated for these SNPs in a sample of healthy controls (n=437). The transcripts significantly regulated by the top SNPs from the GWAS meta-analysis were subsequently tested for differential expression in an independent set ofschizophreniacases and controls (n=202). After correction for multiple testing, the eQTL analysis yielded 40 significant cis-acting effects of the SNPs. Seven of these transcripts show differential expression between cases and controls. Of these, the effect of three genes (RNF5,TRIM26and HLA-DRB3) coincided with the direction expected from meta-analysis findings and were all located within the MHC region. Our results identify new genes of interest and highlight again the involvement of the MHC region inschizophreniasusceptibility. |
| SCZ Keywords | schizophrenia |
| 2 | Behav Brain Funct 2013 -1 9: 40 |
| PMID | 24160291 |
| Title | The impact of the genome-wide supported variant in the cyclin M2 gene on gray matter morphology in schizophrenia. |
| Abstract | Genome-wide significant associations ofschizophreniawith eight SNPs in the CNNM2, MIR137, PCGEM1,TRIM26, CSMD1, MMP16, NT5C2 and CCDC68 genes have been identified in a recent mega-analysis of genome-wide association studies. To date, the role of these SNPs on gray matter (GM) volumes remains unclear. After performing quality control for minor-allele frequency?>?5% using a JPT HapMap sample and our sample, a genotyping call rate?>?95% and Hardy-Weinberg equilibrium testing (p?>?0.01), five of eight SNPs were eligible for analysis. We used a comprehensive voxel-based morphometry (VBM) technique to investigate the effects of these five SNPs on GM volumes between major-allele homozygotes and minor-allele carriers in Japanese patients withschizophrenia(n?=?173) and healthy subjects (n?=?449). The rs7914558 risk variant at CNNM2 was associated with voxel-based GM volumes in the bilateral inferior frontal gyri (right T?=?4.96, p?=?0.0088, left T?=?4.66, p?=?0.031). These peak voxels, which were affected by the variant, existed in the orbital region of the inferior frontal gyri. Individuals with the risk G/G genotype of rs7914558 had smaller GM volumes in the bilateral inferior frontal gyri than carriers of the non-risk A-allele. Although several effects of the genotype and the genotype-diagnosis interaction of other SNPs on GM volumes were observed in the exploratory VBM analyses, these effects did not remain after the FWE-correction for multiple tests (p?>?0.05). Our findings suggest that the genetic variant in the CNNM2 gene could be implicated in the pathogenesis ofschizophreniathrough the GM volumetric vulnerability of the orbital regions in the inferior frontal gyri. |
| SCZ Keywords | schizophrenia |
| 3 | 前> 2014 1 8:331 |
| PMID | 25414627 |
| Title | Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders. |
| Abstract | Major neuropsychiatric disorders are highly 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). We curated a well-vetted list of genes based on large-scale human genetic studies based on the NHGRI catalog of published genome-wide association studies (GWAS). A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (<10(-5)). 22% of genes overlapped two or more disorders. The most widely shared subset of genes-common to five of six disorders-included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4,TRIM26, ZNRD1。使用一套neuroinformatic资源urces, 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 |