| 1 | Lancet 2013 Apr 381: 1371-9 |
|---|---|
| PMID | 23453885 |
| Title | Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. |
| Abstract | Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause. National Institute of Mental Health. |
| SCZ Keywords | schizophrenia |
| 2 | Front Neurosci 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), and schizophrenia (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, 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 |
| 3 | 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 genes ITIH3, 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 entré 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 |
| 4 | Proc. Natl. Acad. Sci. U.S.A. 2014 Jul 111: 9657-62 |
| PMID | 24979789 |
| Title | Identification of gene ontologies linked to prefrontal-hippocampal functional coupling in the human brain. |
| Abstract | Functional interactions between the dorsolateral prefrontal cortex and hippocampus during working memory have been studied extensively as an intermediate phenotype for schizophrenia. Coupling abnormalities have been found in patients, their unaffected siblings, and carriers of common genetic variants associated with schizophrenia, but the global genetic architecture of this imaging phenotype is unclear. To achieve genome-wide hypothesis-free identification of genes and pathways associated with prefrontal-hippocampal interactions, we combined gene set enrichment analysis with whole-genome genotyping and functional magnetic resonance imaging data from 269 healthy German volunteers. We found significant enrichment of the synapse organization and biogenesis gene set. This gene set included known schizophrenia risk genes, such as neural cell adhesion molecule (NRCAM) and calcium channel, voltage-dependent, beta 2 subunit (CACNB2), as well as genes with well-defined roles in neurodevelopmental and plasticity processes that are dysfunctional in schizophrenia and have mechanistic links to prefrontal-hippocampal functional interactions. Our results demonstrate a readily generalizable approach that can be used to identify the neurogenetic basis of systems-level phenotypes. Moreover, our findings identify gene sets in which genetic variation may contribute to disease risk through altered prefrontal-hippocampal functional interactions and suggest a link to both ongoing and developmental synaptic plasticity. |
| SCZ Keywords | schizophrenia |
| 5 | PLoS Genet. 2014 Jun 10: e1004345 |
| PMID | 24901509 |
| Title | Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia. |
| Abstract | In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia. |
| SCZ Keywords | schizophrenia |
| 6 | Curr Mol Pharmacol 2015 -1 8: 32-42 |
| PMID | 25966706 |
| Title | CACNB2: An Emerging Pharmacological Target for Hypertension, Heart Failure, Arrhythmia and Mental Disorders. |
| Abstract | The voltage-gated Cav1.2 calcium channels respond to membrane depolarization by increasing the membrane permeability to Ca(2+), a major signal for cardiac muscle contraction, regulation of vascular tone and CREB-dependent transcriptional activation. CACNB2 is one of the four homologous genes coding for the auxiliary Cav? subunits, which are important modulators of the Ca(2+) channel activity. Five serious mental disorders - autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia, - and three major cardiovascular diseases - hypertension, heart failure and sudden cardiac death, - have recently been linked to the CACNB2 gene coding for the Cav?2 subunits. Here I will focus on the Cav?2-specific molecular determinant ?2-CED as an emerging pharmacological target. |
| SCZ Keywords | schizophrenia |
| 7 | Front Behav Neurosci 2015 -1 9: 141 |
| PMID | 26136667 |
| Title | Comprehensive behavioral analysis of voltage-gated calcium channel beta-anchoring and -regulatory protein knockout mice. |
| Abstract | Calcium (Ca(2+)) influx through voltage-gated Ca(2+) channels (VGCCs) induces numerous intracellular events such as neuronal excitability, neurotransmitter release, synaptic plasticity, and gene regulation. It has been shown that genes related to Ca(2+) signaling, such as the CACNA1C, CACNB2, and CACNA1I genes that encode VGCC subunits, are associated with schizophrenia and other psychiatric disorders. Recently, VGCC beta-anchoring and -regulatory protein (BARP) was identified as a novel regulator of VGCC activity via the interaction of VGCC ? subunits. To examine the role of the BARP in higher brain functions, we generated BARP knockout (KO) mice and conducted a comprehensive battery of behavioral tests. BARP KO mice exhibited greatly reduced locomotor activity, as evidenced by decreased vertical activity, stereotypic counts in the open field test, and activity level in the home cage, and longer latency to complete a session in spontaneous T-maze alteration test, which reached "study-wide significance." Acoustic startle response was also reduced in the mutants. Interestingly, they showed multiple behavioral phenotypes that are seemingly opposite to those seen in the mouse models of schizophrenia and its related disorders, including increased working memory, flexibility, prepulse inhibition, and social interaction, and decreased locomotor activity, though many of these phenotypes are statistically weak and require further replications. These results demonstrate that BARP is involved in the regulation of locomotor activity and, possibly, emotionality. The possibility was also suggested that BARP KO mice may serve as a unique tool for investigating the pathogenesis/pathophysiology of schizophrenia and related disorders. Further evaluation of the molecular and physiological phenotypes of the mutant mice would provide new insights into the role of BARP in higher brain functions. |
| SCZ Keywords | schizophrenia |
| 8 | Mol. Psychiatry 2015 Jul 20: 820-6 |
| PMID | 25869805 |
| Title | Targeting the schizophrenia genome: a fast track strategy from GWAS to clinic. |
| Abstract | The Psychiatric Genomics Consortium-schizophrenia Workgroup (PGC-SCZ) has recently published a genomewide association study (GWAS) identifying >100 genetic loci, encompassing a total of 341 protein-coding genes, attaining genomewide significance for susceptibility to schizophrenia. Given the extremely long time (12-15 years) and expense (>$1 billion) associated with the development of novel drug targets, repurposing of drugs with known and validated targets may be the most expeditious path toward deriving clinical utility from these GWAS findings. In the present study, we examined all genes within loci implicated by the PGC-SCZ GWAS against databases of targets of both approved and registered pharmaceutical compounds. We identified 20 potential schizophrenia susceptibility genes that encode proteins that are the targets of approved drugs. Of these, we prioritized genes/targets that are of clear neuropsychiatric interest and that are also sole members of the linkage disequilibrium block surrounding a PGC-SCZ GWAS hit. In addition to DRD2, 5 genes meet these criteria: CACNA1C, CACNB2, CACNA1I, GRIN2A and HCN1. An additional 20 genes coding for proteins that are the targets of drugs in registered clinical trials, but without approved indications, were also identified. Although considerable work is still required to fully explicate the biological implications of the PGC-SCZ GWAS results, pathways related to these known, druggable targets may represent a promising starting point. |
| SCZ Keywords | schizophrenia |