| 1 | Nippon Rinsho 2009 Jun 67: 1085-9 |
|---|---|
| PMID | 19507497 |
| Title | [Genome wide studies of mental disorders]. |
| Abstract | In these two years, genome wide association studies of SNPs and CNVs in large samples of patients with bipolar disorder or schizophrenia were published. In bipolar disorder, association with SNPs of ANK3 and CACNA1C was found by the combined analysis of three sample sets, which was consistent across three sample sets. In schizophrenia, two deletions, 1q21.1 and 15q13.3, were found to increase the risk of schizophrenia with odds ratios larger than 10. These two deletions are regarderd as the causes of genome diseases that accompany facial dysmorphism and developmental disorders. |
| SCZ Keywords | schizophrenia |
| 2 | Hum. Genet. 2009 Jul 126: 3-12 |
| PMID | 19521722 |
| Title | Genetics of psychosis; insights from views across the genome. |
| Abstract | The major psychotic illnesses, schizophrenia and bipolar disorder (BD), are among the most heritable common disorders, but finding specific susceptibility genes for them has not been straightforward. The reasons are widely assumed to include lack of valid phenotypic definition, absence of good theories of pathophysiology for candidate gene studies, and the involvement of many genes, each making small contributions to population risk. Within the last year or so, a number of genome wide association (GWAS) of schizophrenia and BD have been published. These have produced stronger evidence for association to specific risk loci than have earlier studies, specifically for the zinc finger binding protein 804A (ZNF804A) locus in schizophrenia and for the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) and ankyrin 3, node of Ranvier (ANK3) loci in bipolar disorder. The ZNF804A and CACNA1C loci appear to influence risk for both disorders, a finding that supports the hypothesis that schizophrenia and BD are not aetiologically distinct. In the case of schizophrenia, a number of rare copy number variants have also been detected that have fairly large effect sizes on disease risk, and that additionally influence risk of autism, mental retardation, and other neurodevelopmental disorders. The existing findings point to some likely pathophysiological mechanisms but also challenge current concepts of disease classification. They also provide grounds for optimism that larger studies will reveal more about the origins of these disorders, although currently, very little of the genetic risk of either disorder is explained. |
| SCZ Keywords | schizophrenia |
| 3 | Neuroscience 2009 Nov 164: 331-43 |
| PMID | 19358880 |
| Title | The genetics of bipolar disorder. |
| Abstract | Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) have raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention. |
| SCZ Keywords | schizophrenia |
| 4 | Schizophr Bull 2009 May 35: 482-90 |
| PMID | 19329560 |
| Title | Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder, and mixed (or "schizoaffective") psychoses. |
| Abstract | As a result of improving technologies and greatly increased sample sizes, the last 2 years has seen unprecedented advances in identification of specific genetic risk factors for psychiatric phenotypes. Strong genetic associations have been reported at common polymorphisms within ANK3 and CACNA1C in bipolar disorder and ZNF804A in schizophrenia and a relatively specific association between common variation in GABA(A) receptor genes and cases with features of both bipolar disorder and schizophrenia. Further, the occurrence of rare copy number variants (CNVs) has been shown to be increased in schizophrenia compared with controls. These emerging data provide a powerful resource for exploring the relationship between psychiatric phenotypes and can, and should, be used to inform conceptualization, classification, and diagnosis in psychiatry. It is already clear that, in general, genetic associations are not specific to one of the traditional diagnostic categories. For example, variation at ZNF804A is associated with risk of both bipolar disorder and schizophrenia, and some rare CNVs are associated with risk of autism and epilepsy as well as schizophrenia. These data are not consistent with a simple dichotomous model of functional psychosis and indicate the urgent need for moves toward approaches that (a) better represent the range of phenotypic variation seen in the clinical population and (b) reflect the underlying biological variation that gives rise to the phenotypes. We consider the implications for models of psychosis and the importance of recognizing and studying illness that has prominent affective and psychotic features. We conclude that if psychiatry is to translate the opportunities offered by new research methodologies, we must finally abandon a 19th-century dichotomy and move to a classificatory approach that is worthy of the 21st century. |
| SCZ Keywords | schizophrenia |
| 5 | J Psychiatr Res 2010 Sep 44: 748-53 |
| PMID | 20185149 |
| Title | Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort. |
| Abstract | We have performed a genome-wide association study (GWAS) of schizophrenia in a Norwegian discovery sample of 201 cases and 305 controls (TOP study) with a focused replication analysis in a larger European sample of 2663 cases and 13,780 control subjects (SGENE-plus study). Firstly, the discovery sample was genotyped with Affymetrix Genome-Wide Human SNP Array 6.0 and 572,888 markers were tested for schizophrenia association. No SNPs in the discovery sample attained genome-wide significance (P<8.7 x 10(-8)). Secondly, based on the GWAS data, we selected 1000 markers with the lowest P values in the discovery TOP sample, and tested these (or HapMap-based surrogates) for association in the replication sample. Sixteen loci were associated with schizophrenia (nominal P value<0.05 and concurring OR) in the replication sample. As a next step, we performed a combined analysis of the findings from these two studies, and the strongest evidence for association with schizophrenia was provided for markers rs7045881 on 9p21, rs433598 on 16p12 and rs10761482 on 10q21. The markers are located in PLAA, ACSM1 and ANK3, respectively. PLAA has not previously been described as a susceptibility gene, but 9p21 is implied as a schizophrenia linkage region. ACSM1 has been identified as a susceptibility gene in a previous schizophrenia GWAS study. The association of ANK3 with schizophrenia is intriguing in light of recent associations of ANK3 with bipolar disorder, thereby supporting the hypothesis of an overlap in genetic susceptibility between these psychopathological entities. |
| SCZ Keywords | schizophrenia |
| 6 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Dec 156B: 969-74 |
| PMID | 21972176 |
| Title | Association analysis of ANK3 gene variants in nordic bipolar disorder and schizophrenia case-control samples. |
| Abstract | Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case-control sample (N = 854/2,614). Due to evidence of genetic overlap between BD and schizophrenia (SZ), we also genotyped these three SNPs in a Scandinavian SZ case-control sample (N = 1,073/2,919). Combining our Scandinavian samples with an Icelandic sample (N = 435 BD cases, 651 SZ cases, and 11,491 healthy controls), we found rs10994336 and rs9804190 to be nominally significantly associated with BD in this combined Nordic BD sample (N = 1,289/14,105). Nominal P was 0.015/0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected P = 0.044/0.053) and 0.023 for rs9804190 (Bonferroni corrected P = 0.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case-control sample (N = 1,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved. |
| SCZ Keywords | schizophrenia |
| 7 | 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 in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for 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 other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)). |
| SCZ Keywords | schizophrenia |
| 8 | World J. Biol. Psychiatry 2011 Aug 12: 392-7 |
| PMID | 21767209 |
| Title | ANK3, CACNA1C and ZNF804A gene variants in bipolar disorders and psychosis subphenotype. |
| Abstract | OBJECTIVES. The ANK3, CACNA1C and ZNF804A genes have been implicated in both bipolar disorders (BPD) and schizophrenia (SCZ). It has been suggested that BPD with psychosis may be a clinical manifestation of genes overlapping between BPD and SCZ. We therefore tested the association of these genes with BPD in a large family-based sample, and then dissected the phenotype into psychosis present or absent subgroups. METHODS. We genotyped four high interest single nucleotide polymorphisms from ANK3 (rs10994336, rs9804190), CACNA1C (rs1006737), and ZNF804A (rs1344706). Family based association testing (FBAT) was performed on 312 families, and within psychotic (N = 158) and non-psychotic BPD (N = 119) subgroups. RESULTS. In the whole sample, we found a nominal association in ZNF804A (rs1344706, P = 0.046), and a trend in CACNA1C (rs1006737, P = 0.077). In the psychotic BPD subgroup, as hypothesized, stronger signals were observed in ZNF804A (P = 0.019) and CACNA1C (P = 0.017). We found no association in the ANK3 markers, but the rs10994336 variant was nominally associated with non-psychotic BPD (P = 0.046). Exploratory analysis revealed the rs1344706 variant was also implicated in suicide-attempt behaviour (P = 0.038). CONCLUSIONS. These tentative results are consistent with the hypothesis that the subphenotype of BPD with psychosis may represent a clinical manifestation of shared genetic liability between BPD and SCZ. |
| SCZ Keywords | schizophrenia |
| 9 | BMC Psychiatry 2011 -1 11: 103 |
| PMID | 21702894 |
| Title | Is Ankyrin a genetic risk factor for psychiatric phenotypes? |
| Abstract | Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression. We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes. We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification. Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases. |
| SCZ Keywords | schizophrenia |
| 10 | Bipolar Disord 2011 May 13: 250-9 |
| PMID | 21676128 |
| Title | The CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males. |
| Abstract | The rs10994336 ANK3 and rs1006737 CACNA1C genetic variants have recently been identified as the most consistent, genome-wide significant risk factors for bipolar disorder, while the CACNA1C variant has also been associated with schizophrenia and major depression. The aim of this study was to examine the phenotypic consequences of the risk CACNA1C and ANK3 alleles in a large homogeneous cohort of healthy young males. We recruited 703 randomly selected, healthy army conscripts (mean age 22.1 ± 3.0 years) from the first wave of the Learning on Genetics of schizophrenia project in Heraklion, Crete. Of those recruited, 530 subjects entered and completed the study. Subjects were assessed for prepulse inhibition (PPI), startle reactivity, neuropsychology, and personality. ? UNPHASED analysis revealed that the rs1006737 A-allele was associated with lower extraversion and higher harm avoidance, trait anxiety, and paranoid ideation, while the rs10994336 T-allele was associated with lower novelty seeking and behavioral activation scores (p < 0.01). Both alleles were associated with high startle reactivity (p < 0.05). There were no significant associations with any cognitive task performance or PPI. The CACNA1C genotype was associated with proneness to anxiety and negative mood, while the ANK3 genotype was associated with proneness to anhedonia. Both risk genotypes were associated with high startle reactivity, suggesting a role of these polymorphisms in threat/stress signal processing, probably in the hippocampus and/or amygdala. None of the risk genotypes affected sensorimotor gating or behavioral performance in an extensive battery of executive function tests in this cohort of healthy males. |
| SCZ Keywords | schizophrenia |
| 11 | Hum. Mol. Genet. 2011 Jan 20: 387-91 |
| PMID | 21037240 |
| Title | Most genome-wide significant susceptibility loci for schizophrenia and bipolar disorder reported to date cross-traditional diagnostic boundaries. |
| Abstract | Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger binding protein 804A (ZNF804A), as showing trans-disorder effects, and the same is true for one of the best supported bipolar loci, calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) which has also been associated with schizophrenia. We have undertaken a cross-phenotype study based upon the remaining variants that show genome-wide evidence for association in large schizophrenia and BD meta-analyses. These comprise in schizophrenia, SNPs in or in the vicinity of transcription factor 4 (TCF4), neurogranin (NRGN) and an extended region covering the MHC locus on chromosome 6. For BD, the strongly supported variants are in the vicinity of ankyrin 3, node of Ranvier (ANK3) and polybromo-1 (PBRM1). Using data sets entirely independent of their original discoveries, we observed strong evidence that the PBRM1 locus is also associated with schizophrenia (P = 0.00015) and nominally significant evidence (P < 0.05) that the NRGN and the extended MHC region are associated with BD. Moreover, considering this highly restricted set of loci as a group, the evidence for trans-disorder effects is compelling (P = 4.7 × 10(-5)). Including earlier reported data for trans-disorder effects for ZNF804A and CACNA1C, six out of eight of the most robustly associated loci for either disorder show trans-disorder effects. |
| SCZ Keywords | schizophrenia |
| 12 | Hum. Mutat. 2012 Dec 33: 1635-8 |
| PMID | 22865819 |
| Title | Mutations of ANK3 identified by exome sequencing are associated with autism susceptibility. |
| Abstract | Autism spectrum disorders (ASDs) are common neurodevelopmental disorders with a strong genetic etiology. However, due to the extreme genetic heterogeneity of ASDs, traditional approaches for gene discovery are challenging. Next-generation sequencing technologies offer an opportunity to accelerate the identification of the genetic causes of ASDs. Here, we report the results of whole-exome sequence in a cohort of 20 ASD patients. By extensive bioinformatic analysis, we identified novel mutations in seven genes that are implicated in synaptic function and neurodevelopment. After sequencing an additional 47 ASD samples, we identified three different missense mutations in ANK3 in four unrelated ASD patients, one of which, c.4705T>G (p.S1569A), is a de novo mutation. Given the fact that ANK3 has been shown to strongly associate with schizophrenia and bipolar disorder, our findings support an association between ANK3 mutations and ASD susceptibility and imply a shared molecular pathophysiology between ASDs and other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 13 | Cell 2012 Apr 149: 525-37 |
| PMID | 22521361 |
| Title | Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. |
| Abstract | Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages. |
| SCZ Keywords | schizophrenia |
| 14 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Dec 159B: 997-1005 |
| PMID | 23109352 |
| Title | ANK3 as a risk gene for schizophrenia: new data in Han Chinese and meta analysis. |
| Abstract | Histological and neuroimaging evidence supports the hypothesis that neuronal disconnectivity may be involved in the pathogenesis of schizophrenia. A genome-wide association study (GWAS) showed a single nucleotide polymorphism (SNP), rs10761482 in ankyrin 3 (ANK3), a major neuron-enriched gene, was associated with schizophrenia although inconsistent results had been reported. Two meta analyses reported another SNP rs10994336 in ANK3 gene confers risk to bipolar disorder (BD). Due to evidence of genetic overlap between schizophrenia and BD, we investigated common findings by analyzing the association of ANK3 polymorphisms (rs10761482, rs10994336, and two missenses, rs3808942 and rs3808943) with schizophrenia, using the Han Chinese population. A total of 516 schizophrenia cases, 400 controls, and 81 trios of early onset schizophrenia were recruited for association studies. Furthermore, the published datasets were combined with our results to determine the effect of the loci on schizophrenia. Our association study showed the frequencies of C allele of rs10761482 and T allele of rs10994336 were higher in patients than in controls. Furthermore, allele condition analyses indicated the association signal observed at rs10761482 and rs10994336 was independent. A haplotype analysis revealed the rs10761482-rs3808942-rs3808943 haplotype was associated with schizophrenia. The frequency of the T-T-T haplotype was higher in patients than in controls. In the transmission disequilibrium test analysis, the C allele of rs10761482 and the rs10761482-rs3808942-rs3808943 haplotype were preferentially transmitted in the trios. Meta analysis incorporating previous and current studies also showed rs10761482 and rs10994336 were associated with schizophrenia. We conclude that ANK3 gene has a major influence on susceptibility to schizophrenia across populations. |
| SCZ Keywords | schizophrenia |
| 15 | Neurosci Biobehav Rev 2012 Jan 36: 556-71 |
| PMID | 21946175 |
| Title | Genome wide association studies (GWAS) and copy number variation (CNV) studies of the major psychoses: what have we learnt? |
| Abstract | schizophrenia (SZ) and bipolar disorder (BPD) have high heritabilities and are clinically and genetically complex. Genome wide association studies (GWAS) and studies of copy number variations (CNV) in SZ and BPD have allowed probing of their underlying genetic risks. In this systematic review, we assess extant genetic signals from published GWAS and CNV studies of SZ and BPD up till March 2011. Risk genes associated with SZ at genome wide significance level (p value<7.2 × 10(-8)) include zinc finger binding protein 804A (ZNF804A), major histocompatibility (MHC) region on chromosome 6, neurogranin (NRGN) and transcription factor 4 (TCF4). Risk genes associated with BPD include ankyrin 3, node of Ranvier (ANK3), calcium channel, voltage dependent, L type, alpha 1C subunit (CACNA1C), diacylglycerol kinase eta (DGKH), gene locus on chromosome 16p12, and polybromo-1 (PBRM1) and very recently neurocan gene (NCAN). Possible common genes underlying psychosis include ZNF804A, CACNA1C, NRGN and PBRM1. The CNV studies suggest that whilst CNVs are found in both SZ and BPD, the large deletions and duplications are more likely found in SZ rather than BPD. The validation of any genetic signal is likely confounded by genetic and phenotypic heterogeneities which are influenced by epistatic, epigenetic and gene-environment interactions. There is a pressing need to better integrate the multiple research platforms including systems biology computational models, genomics, cross disorder phenotyping studies, transcriptomics, proteomics, metabolomics, neuroimaging and clinical correlations in order to get us closer to a more enlightened understanding of the genetic and biological basis underlying these potentially crippling conditions. |
| SCZ Keywords | schizophrenia |
| 16 | Arch. Gen. Psychiatry 2012 Jan 69: 7-15 |
| PMID | 21893642 |
| Title | Molecular and genetic evidence for abnormalities in the nodes of Ranvier in schizophrenia. |
| Abstract | Genetic, neuroimaging, and molecular neurobiological evidence support the hypothesis that the disconnectivity syndrome in schizophrenia (SZ) could arise from failures of saltatory conduction and abnormalities at the nodes of Ranvier (NOR) interface where myelin and axons interact. To identify abnormalities in the expression of oligodendroglial genes and proteins that participate in the formation, maintenance, and integrity of the NOR in SZ. The messenger RNA (mRNA) expression levels of multiple NOR genes were quantified in 2 independent postmortem brain cohorts of individuals with SZ, and generalizability to protein expression was confirmed. The effect of the ANK3 genotype on the mRNA expression level was tested in postmortem human brain. Case-control analysis tested the association of the ANK3 genotype with SZ. The ANK3 genotype's influence on cognitive task performance and functional magnetic resonance imaging activation was tested in 2 independent cohorts of healthy individuals. Research hospital. Patients Postmortem samples from patients with SZ and healthy controls were used for the brain expression study (n = 46) and the case-control analysis (n = 272). Healthy white men and women participated in the cognitive (n = 513) and neuroimaging (n = 52) studies. The mRNA and protein levels in postmortem brain samples, genetic association with schizophrenia, cognitive performance, and blood oxygenation level-dependent functional magnetic resonance imaging. The mRNA expression of multiple NOR genes was decreased in schizophrenia. The ANK3 rs9804190 C allele was associated with lower ANK3 mRNA expression levels, higher risk for SZ in the case-control cohort, and poorer working memory and executive function performance and increased prefrontal activation during a working memory task in healthy individuals. These results point to abnormalities in the expression of genes and protein associated with the integrity of the NOR and suggest them as substrates for the disconnectivity syndrome in SZ. The association of ANK3 with lower brain mRNA expression levels implicates a molecular mechanism for its genetic, clinical, and cognitive associations with SZ. |
| SCZ Keywords | schizophrenia |
| 17 | Neuropsychiatr Dis Treat 2013 -1 9: 1573-82 |
| PMID | 24143106 |
| Title | Evidence for single nucleotide polymorphisms and their association with bipolar disorder. |
| Abstract | Bipolar disorder (BD) is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs). Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1]) to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3]) replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data. |
| SCZ Keywords | schizophrenia |
| 18 | J Affect Disord 2013 Oct 151: 291-7 |
| PMID | 23820096 |
| Title | No evidence for association between bipolar disorder risk gene variants and brain structural phenotypes. |
| Abstract | While recent genome-wide association studies have identified several new bipolar disorder (BD) risk variants, structural imaging studies have reported enlarged ventricles and volumetric reductions among the most consistent findings. We investigated whether these genetic risk variants could explain some of the structural brain abnormalities in BD. In a sample of 517 individuals (N=121 BD cases, 116 SZ cases, 61 other psychosis cases and 219 healthy controls), we tested the potential association between nine SNPs in the genes CACNA1C, ANK3, ODZ4 and SYNE1 and eight brain structural measures found to be altered in BD, and if these were specifically affecting the BD sample. We also assessed the polygenic effect of all these 9 SNPs on the brain phenotypes. Our most significant result was an association between the risk allele A in CACNA1C SNP rs4775913 and decreased cerebellar volume (pnom.=0.0075) in the total sample, which did not remain significant after multiple testing correction (pthreshold<0.0064). There was no evidence for diagnostic specificity for this association in the BD group. Further, no polygenic effect of these 9 SNPs was observed. Low statistical power might increase our type II error rate. The present findings indicate that these risk SNPs do not explain a large proportion of the structural brain alterations in BD. Thus, these genes which are all related to neuronal functions must be involved in other pathophysiological aspects of BD development. |
| SCZ Keywords | schizophrenia |
| 19 | Psychoneuroendocrinology 2013 Oct 38: 2249-57 |
| PMID | 23796624 |
| Title | The ankyrin-3 gene is associated with posttraumatic stress disorder and externalizing comorbidity. |
| Abstract | The ankyrin 3 gene (ANK3) produces the ankyrin G protein that plays an integral role in regulating neuronal activity. Previous studies have linked ANK3 to bipolar disorder and schizophrenia. A recent mouse study suggests that ANK3 may regulate behavioral disinhibition and stress reactivity. This led us to hypothesize that ANK3 might also be associated with stress-related psychopathology such as posttraumatic stress disorder (PTSD), as well as disorders of the externalizing spectrum such as antisocial personality disorder and substance-related disorders that are etiologically linked to impulsivity and temperamental disinhibition. We examined the possibility of association between ANK3 SNPs and both PTSD and externalizing (defined by a factor score representing a composite of adult antisociality and substance abuse) in a cohort of white non-Hispanic combat veterans and their intimate partners (n=554). Initially, we focused on rs9804190-a SNP previously reported to be associated with bipolar disorder, schizophrenia, and ankyrin G expression in brain. Then we examined 358 additional ANK3 SNPs utilizing a multiple-testing correction. rs9804190 was associated with both externalizing and PTSD (p=0.028 and p=0.042 respectively). Analysis of other ANK3 SNPs identified several that were more strongly associated with either trait. The most significant association with externalizing was observed at rs1049862 (p=0.00040, pcorrected=0.60). The most significant association with PTSD (p=0.00060, pcorrected=0.045) was found with three SNPs in complete linkage disequilibrium (LD)-rs28932171, rs11599164, and rs17208576. These findings support a role of ANK3 in risk of stress-related and externalizing disorders, beyond its previous associations with bipolar disorder and schizophrenia. |
| SCZ Keywords | schizophrenia |
| 20 | Neuroimage 2013 Dec 83: 384-96 |
| PMID | 23727316 |
| Title | Guided exploration of genomic risk for gray matter abnormalities in schizophrenia using parallel independent component analysis with reference. |
| Abstract | One application of imaging genomics is to explore genetic variants associated with brain structure and function, presenting a new means of mapping genetic influences on mental disorders. While there is growing interest in performing genome-wide searches for determinants, it remains challenging to identify genetic factors of small effect size, especially in limited sample sizes. In an attempt to address this issue, we propose to take advantage of a priori knowledge, specifically to extend parallel independent component analysis (pICA) to incorporate a reference (pICA-R), aiming to better reveal relationships between hidden factors of a particular attribute. The new approach was first evaluated on simulated data for its performance under different configurations of effect size and dimensionality. Then pICA-R was applied to a 300-participant (140 schizophrenia (SZ) patients versus 160 healthy controls) dataset consisting of structural magnetic resonance imaging (sMRI) and single nucleotide polymorphism (SNP) data. Guided by a reference SNP set derived from ANK3, a gene implicated by the Psychiatric Genomic Consortium SZ study, pICA-R identified one pair of SNP and sMRI components with a significant loading correlation of 0.27 (p=1.64×10(-6)). The sMRI component showed a significant group difference in loading parameters between patients and controls (p=1.33×10(-15)), indicating SZ-related reduction in gray matter concentration in prefrontal and temporal regions. The linked SNP component also showed a group difference (p=0.04) and was predominantly contributed to by 1030 SNPs. The effect of these top contributing SNPs was verified using association test results of the Psychiatric Genomic Consortium SZ study, where the 1030 SNPs exhibited significant SZ enrichment compared to the whole genome. In addition, pathway analyses indicated the genetic component majorly relating to neurotransmitter and nervous system signaling pathways. Given the simulation and experiment results, pICA-R may prove a promising multivariate approach for use in imaging genomics to discover reliable genetic risk factors under a scenario of relatively high dimensionality and small effect size. |
| SCZ Keywords | schizophrenia |
| 21 | Hum. Mol. Genet. 2013 May 22: 1960-70 |
| PMID | 23390136 |
| Title | Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. |
| Abstract | AnkyrinG, encoded by the ANK3 gene, is involved in neuronal development and signaling. It has previously been implicated in bipolar disorder and schizophrenia by association studies. Most recently, de novo missense mutations in this gene were identified in autistic patients. However, the causative nature of these mutations remained controversial. Here, we report inactivating mutations in the Ankyrin 3 (ANK3) gene in patients with severe cognitive deficits. In a patient with a borderline intelligence, severe attention deficit hyperactivity disorder (ADHD), autism and sleeping problems, all isoforms of the ANK3 gene, were disrupted by a balanced translocation. Furthermore, in a consanguineous family with moderate intellectual disability (ID), an ADHD-like phenotype and behavioral problems, we identified a homozygous truncating frameshift mutation in the longest isoform of the same gene, which represents the first reported familial mutation in the ANK3 gene. The causality of ANK3 mutations in the two families and the role of the gene in cognitive function were supported by memory defects in a Drosophila knockdown model. Thus we demonstrated that ANK3 plays a role in intellectual functioning. In addition, our findings support the suggested association of ANK3 with various neuropsychiatric disorders and illustrate the genetic and molecular relation between a wide range of neurodevelopmental disorders. |
| SCZ Keywords | schizophrenia |
| 22 | Neuron 2014 Oct 84: 399-415 |
| PMID | 25374361 |
| Title | Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapses. |
| Abstract | Recent evidence implicates glutamatergic synapses as key pathogenic sites in psychiatric disorders. Common and rare variants in the ANK3 gene, encoding ankyrin-G, have been associated with bipolar disorder, schizophrenia, and autism. Here we demonstrate that ankyrin-G is integral to AMPAR-mediated synaptic transmission and maintenance of spine morphology. Using superresolution microscopy we find that ankyrin-G forms distinct nanodomain structures within the spine head and neck. At these sites, it modulates mushroom spine structure and function, probably as a perisynaptic scaffold and barrier within the spine neck. Neuronal activity promotes ankyrin-G accumulation in distinct spine subdomains, where it differentially regulates NMDA receptor-dependent plasticity. These data implicate subsynaptic nanodomains containing a major psychiatric risk molecule, ankyrin-G, as having location-specific functions and open directions for basic and translational investigation of psychiatric risk molecules. |
| SCZ Keywords | schizophrenia |
| 23 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Oct 54: 157-62 |
| PMID | 24914473 |
| Title | Genetic association of LMAN2L gene in schizophrenia and bipolar disorder and its interaction with ANK3 gene polymorphism. |
| Abstract | Recent studies have shown that bipolar disorder (BPD) and schizophrenia (SZ) share some common genetic risk factors. This study aimed to examine the association between candidate single nucleotide polymorphisms (SNPs) identified from genome-wide association studies (GWAS) and risk of BPD and SZ. A total of 715 patients (244 BPD and 471 SZ) and 593 controls were genotyped using the Sequenom MassARRAY platform. We showed a positive association between LMAN2L (rs6746896) and risk of both BPD and SZ in a pooled population (P-value=0.001 and 0.009, respectively). Following stratification by ethnicity, variants of the ANK3 gene (rs1938516 and rs10994336) were found to be associated with BPD in Malays (P-value=0.001 and 0.006, respectively). Furthermore, an association exists between another variant of LMAN2L (rs2271893) and SZ in the Malay and Indian ethnic groups (P-value=0.003 and 0.002, respectively). Gene-gene interaction analysis revealed a significant interaction between the ANK3 and LMAN2L genes (empirical P=0.0107). Significant differences were shown between patients and controls for two haplotype frequencies of LMAN2L: GA (P=0.015 and P=0.010, for BPD and SZ, respectively) and GG (P=0.013 for BPD). Our study showed a significant association between LMAN2L and risk of both BPD and SZ. |
| SCZ Keywords | schizophrenia |
| 24 | Br J Psychiatry 2014 Sep 205: 244-5 |
| PMID | 24809399 |
| Title | ANK3 gene expression in bipolar disorder and schizophrenia. |
| Abstract | ANK3 gene variants have consistently been associated with bipolar spectrum disorder and schizophrenia spectrum disorder. However, the relevance of its encoded protein, ankyrin-3, in these disorders remains elusive. Here, we show that ANK3 gene expression in blood is significantly increased in bipolar disorder and schizophrenia compared with healthy controls. Additionally, we identified potential cis-acting expression quantitative trait loci located close to the transcription start site of one of the isoforms of the gene. These findings suggest that ANK3 mRNA is an interesting marker for further investigation of the underlying mechanisms in psychotic disorders. |
| SCZ Keywords | schizophrenia |
| 25 | Shanghai Arch Psychiatry 2014 Oct 26: 288-93 |
| PMID | 25477722 |
| Title | Case control study of association between the ANK3 rs10761482 polymorphism and schizophrenia in persons of Uyghur nationality living in Xinjiang China. |
| Abstract | The rs10761482 polymorphism of the ANK3 gene has been associated with the occurrence of schizophrenia. Assess the relationship between the ANK3 gene and schizophrenia in individuals of Uyghurian descent. A total of 630 patients with schizophrenia and 535 healthy controls of Uyghur descent were genotyped for the ANK3 gene rs10761482 locus using Taqman probe technology. SHEsis and SPSS17.0 software were used for data analysis. There were no significant differences in the genotype or allele frequencies between the case group and control group. Within the case group there was no relationship between gender or age of onset of schizophrenia and the genotype or allele frequencies. Separate analyses among men and among women also failed to identify significant differences in the allele and genotype frequencies between cases and controls or between patients with adolescent-onset schizophrenia and those with adult-onset schizophrenia. Our findings do not support previous reports about the relationship of the ANK3 gene and schizophrenia. In the Uyghur nationality group recruited for this study there was no significant association between the ANK3 gene rs10761482 polymorphism and schizophrenia. If these results are replicated in further studies, then the focus should change to understanding why this widely acknowledged association does not exist in this particular ethnic group. |
| SCZ Keywords | schizophrenia |
| 26 | 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 |
| 27 | Curr Psychiatry Rep 2014 Nov 16: 493 |
| PMID | 25194313 |
| Title | New developments in the genetics of bipolar disorder. |
| Abstract | The last several years have been breakthrough ones in bipolar disorder (BPD) genetics, as the field has identified robust risk variants for the first time. Leading the way have been genome-wide association studies (GWAS) that have assessed common genetic markers across very large groups of patients and controls. These have resulted in findings in genes including ANK3, CACNA1C, SYNE1, ODZ4, and TRANK1. Additional studies have begun to examine the biology of these genes and how risk variants influence aspects of brain and behavior that underlie BPD. For example, carriers of the CACNA1C risk variant have been found to exhibit hippocampal and anterior cingulate dysfunction during episodic memory recall. This work has shed additional light on the relationship of bipolar susceptibility variants to other disorders, particularly schizophrenia. Even larger BPD GWAS are expected with samples now amassed of 21,035 cases and 28,758 controls. Studies have examined the pharmacogenomics of BPD with studies of lithium response, yielding high profile results that remain to be confirmed. The next frontier in the field is the identification of rare bipolar susceptibility variants through large-scale DNA sequencing. While only a couple of papers have been published to date, many studies are underway. The Bipolar Sequencing Consortium has been formed to bring together all of the groups working in this area, and to perform meta-analyses of the data generated. The consortium, with 13 member groups, now has exome data on ~3,500 cases and ~5,000 controls, and on ~162 families. The focus will likely shift within several years from exome data to whole genome data as costs of obtaining such data continue to drop. Gene-mapping studies are now providing clear results that provide insights into the pathophysiology of the disorder. Sequencing studies should extend this process further. Findings could eventually set the stage for rational therapeutic development. |
| SCZ Keywords | schizophrenia |
| 28 | 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) and schizophrenia (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) and 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 the ITIH3/4-region in a combined group of patients with BD, SCZ and related psychosis spectrum disorders. This may be useful in understanding molecular mechanisms of suicidal behaviour in severe mental disorders, although replication is warranted. |
| SCZ Keywords | schizophrenia |
| 29 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Apr 50: 110-5 |
| PMID | 24361380 |
| Title | Genetic modulation of working memory deficits by ankyrin 3 gene in schizophrenia. |
| Abstract | Neuropsychological endophenotype approach is an emerging strategy in schizophrenia research to understand and identify the functional importance of genetically transmitted, brain-based deficits present in this disorder. Accumulating evidence indicated that working memory deficit is a core neuropsychological dysfunction in schizophrenia and a primary endophenotype indexing the liability to develop schizophrenia. Genetic variation in ankyrin 3 gene (ANK3) is likely to have widespread cognitive effects. Our previous study has identified a significant association of ANK3 SNPs and schizophrenia. In this study, we aimed to examine whether the schizophrenia-risk SNPs within ANK3 may affect working memory deficits in schizophrenia patients. Herein, we assess the working memory performance in 163 patients with first-episode, antipsychotic-naļve schizophrenia and 42 sex, age-matched healthy subjects using N-back task. Two SNPs rs10761482 and rs10994336 were genotyped among the patients and 209 controls. Our results showed that schizophrenia patients showed significantly poorer performance than healthy controls on N-back task (ps<0.01). After adjusting for the scores of intelligence quotient, memory quotient and the demographic factors, there was a significant genotype effect of the rs10994336 on the accuracy rate and reaction time of 2-back item (p=0.048 and 0.024, respectively). Post-hoc analyses showed that patients with rs10994336T/T genotype had significantly lower accuracy rate and more reaction time at 2-back task than those with T/C and C/C genotypes. The association of SNP rs10994336 with schizophrenia was replicated in our sample (genotypic p=0.024 and allelic p=0.006). However, we did not find any significant association of rs10761482 with schizophrenia and parameters in N-back task. Our results indicated that genetic variation within ANK3 may exert gene-specific modulating effects on working memory deficits in schizophrenia. |
| SCZ Keywords | schizophrenia |
| 30 | J Psychiatry Neurosci 2014 Jan 39: 31-9 |
| PMID | 24016415 |
| Title | Association of a risk allele of ANK3 with cognitive performance and cortical thickness in patients with first-episode psychosis. |
| Abstract | The gene ANK3 is implicated in bipolar disorder and schizophrenia. The present study investigated the influence of this gene on cognitive performance and brain structure among individuals with first-episode psychosis (FEP). The brief illness duration of an FEP sample makes it well suited for studying the effects of genetic variation. We genotyped 2 single nucleotide polymorphisms (SNPs; rs1938526 and rs10994336) in ANK3 in patients with FEP. Multivariate analysis of variance compared risk allele carriers and noncarriers on 6 domains of cognition consistent with MATRICS consensus. A subsample of 82 patients was assessed using magnetic resonance imaging. We compared brain structure between carriers and noncarriers using cortical thickness analysis and voxel-based morphometry on white matter. In the 173 patients with FEP included in our study, rs1938526 and rs10994336 were in very high linkage disequilibrium (d' = 0.95), and analyses were therefore only carried out on the SNP (rs1938526) with the highest minor allele frequency (G). Allele G of rs1938526, was associated with lower cognitive performance across domains (F6,164 = 2.38, p = 0.030) and significantly lower scores on the domains of verbal memory (p = 0.015), working memory (p = 0.006) and attention (p = 0.019). The significant effects of this SNP on cognition were not maintained when controlling for IQ. Cortical thinning was observed in risk allele carriers at diverse sites across cortical lobes bilaterally at a threshold of p < 0.01, false discovery rate-corrected. Risk-allele carriers did not show any regions of reduced white matter volume. The sample size is modest given that a low-frequency variant was being examined. The ANK3 risk allele rs1938526 appears to be associated with general cognitive impairment and widespread cortical thinning in patients with FEP. |
| SCZ Keywords | schizophrenia |
| 31 | Biol. Psychiatry 2015 Nov -1: -1 |
| PMID | 26682468 |
| Title | A Loss-of-Function Variant in a Minor Isoform of ANK3 Protects Against Bipolar Disorder and Schizophrenia. |
| Abstract | Ankyrin-3 (ANK3) was one of the first genes to reach significance in a bipolar disorder genome-wide association study. Many subsequent association studies confirmed this finding and implicated this gene in schizophrenia. However, the exact nature of the role of ANK3 in the pathophysiology remains elusive. In particular, the specific isoforms involved and the nature of the imbalance are unknown. We genotyped a Norwegian sample of 402 patients with bipolar disorder, 293 patients with schizophrenia, and 330 healthy control subjects genome-wide with the Illumina Human Exome BeadChip. We performed allelic association tests at the genome-wide and gene levels and found a significantly associated single nucleotide polymorphism in a splice site of ANK3. We replicated this finding in two other samples and studied the functional effect of this single nucleotide polymorphism by performing quantitative polymerase chain reaction on the affected exon junction in complementary DNA from blood total RNA. The splice site single nucleotide polymorphism (rs41283526) is located in an alternatively spliced exon of ANK3 and has a strong and significant protective effect against bipolar disorder (odds ratio = .31) and schizophrenia (odds ratio = .21). The minor allele of rs41283526 is a loss-of-function variant that disables the correct splicing of the transcript. Data from the BrainSpan human developmental transcriptome show that the exon bearing this variant is expressed only in a minor isoform of ANK3, the transcription of which is initiated in early adolescence. Our results suggest that an elevated expression of this transcript starting in adolescence may be an important factor in the pathophysiology of schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia |
| 32 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Dec 168: 637-48 |
| PMID | 26227746 |
| Title | Genetic analysis of SNPs in CACNA1C and ANK3 gene with schizophrenia: A comprehensive meta-analysis. |
| Abstract | Recently, genome-wide association studies (GWAS), meta-analyses, and replication studies focusing on bipolar disorder (BD) have implicated the ?-1C subunit of the L-type voltage-dependent calcium channel (CACNA1C) and ankyrin 3 (ANK3) genes in BD. Based on the hypothesis that both schizophrenia (SZ) and BD may share some common genetic risk factors, we investigated the association of CACNA1C and ANK3 with SZ using meta-analytic techniques, combining all published data up to April 2015. Nine teams, including four European decent samples and five Asian samples, contributed 14,141 cases and 30,679 controls for the analysis of CACNA1C rs1006737 and SZ. A significant difference was identified between patients and controls for the A-allele of rs1006737 in combined studies (Z?=?6.02, P?=?1.74E-09), in European studies (Z?=?4.08, P?=?4.50E-05), and in Asian studies (Z?=?4.60, P?=?4.22E-06). Meanwhile, for the T-allele of ANK3 rs10761482 (1,794 cases versus 1,395 controls), a significant association was observed in combined samples (Z?=?2.06, P?=?0.04) and in Asian samples (Z?=?3.10, P?=?0.002). In summary, our study provides further evidence for the positive association of CACNA1C and ANK3 with SZ. These results support the hypothesis that both SZ and BD share common genetic risk factors. Further research is needed to examine the functions of CACNA1C and ANK3, and their interacting partners in the molecular, developmental, and pathophysiological processes in SZ. |
| SCZ Keywords | schizophrenia |
| 33 | Transl Psychiatry 2015 -1 5: e552 |
| PMID | 25897833 |
| Title | Genome-wide association study of behavioural and psychiatric features in human prion disease. |
| Abstract | Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves. |
| SCZ Keywords | schizophrenia |
| 34 | Mol. Psychiatry 2015 Mar 20: 388-97 |
| PMID | 24821222 |
| Title | Ankyrin-G regulates neurogenesis and Wnt signaling by altering the subcellular localization of ?-catenin. |
| Abstract | Ankyrin-G is a scaffolding protein required for the formation of the axon initial segment in neurons. Recent genome-wide association studies and whole-exome sequencing have identified ANK3, the gene coding for ankyrin-G, to be a risk gene for multiple neuropsychiatric disorders, such as bipolar disorder, schizophrenia and autism spectrum disorder. Here, we describe a novel role for ankyrin-G in neural progenitor proliferation in the developing cortex. We found that ankyrin-G regulates canonical Wnt signaling by altering the subcellular localization and availability of ?-catenin in proliferating cells. Ankyrin-G loss-of-function increases ?-catenin levels in the nucleus, thereby promoting neural progenitor proliferation. Importantly, abnormalities in proliferation can be rescued by reducing Wnt pathway signaling. Taken together, these results suggest that ankyrin-G is required for proper brain development. |
| SCZ Keywords | schizophrenia |
| 35 | Psychol Med 2015 -1 45: 2461-80 |
| PMID | 25858580 |
| Title | What is the impact of genome-wide supported risk variants for schizophrenia and bipolar disorder on brain structure and function? A systematic review. |
| Abstract | The powerful genome-wide association studies (GWAS) revealed common mutations that increase susceptibility for schizophrenia (SZ) and bipolar disorder (BD), but the vast majority were not known to be functional or associated with these illnesses. To help fill this gap, their impact on human brain structure and function has been examined. We systematically discuss this output to facilitate its timely integration in the psychosis research field; and encourage reflection for future research. Irrespective of imaging modality, studies addressing the effect of SZ/BD GWAS risk genes (ANK3, CACNA1C, MHC, TCF4, NRGN, DGKH, PBRM1, NCAN and ZNF804A) were included. Most GWAS risk variations were reported to affect neuroimaging phenotypes implicated in SZ/BD: white-matter integrity (ANK3 and ZNF804A), volume (CACNA1C and ZNF804A) and density (ZNF804A); grey-matter (CACNA1C, NRGN, TCF4 and ZNF804A) and ventricular (TCF4) volume; cortical folding (NCAN) and thickness (ZNF804A); regional activation during executive tasks (ANK3, CACNA1C, DGKH, NRGN and ZNF804A) and functional connectivity during executive tasks (CACNA1C and ZNF804A), facial affect recognition (CACNA1C and ZNF804A) and theory-of-mind (ZNF804A); but inconsistencies and non-replications also exist. Further efforts such as standardizing reporting and exploring complementary designs, are warranted to test the reproducibility of these early findings. |
| SCZ Keywords | schizophrenia |