Showing papers by "Evangelos Vassos published in 2011"
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deCODE genetics1, Copenhagen University Hospital2, Ludwig Maximilian University of Munich3, University of Bonn4, Utrecht University5, GlaxoSmithKline6, University of Aberdeen7, King's College London8, Radboud University Nijmegen Medical Centre9, University of Verona10, University of Oslo11, University of California, Los Angeles12, Heidelberg University13, Wellcome Trust Sanger Institute14, Broad Institute15
TL;DR: It is concluded that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.
Abstract: Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.
258 citations
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deCODE genetics1, Utrecht University2, University of Oslo3, University of Copenhagen4, Aarhus University5, Oslo University Hospital6, Wellcome Trust Sanger Institute7, Max Planck Society8, University of Tübingen9, University of Bonn10, Heidelberg University11, King's College London12, Ludwig Maximilian University of Munich13, University of Aberdeen14, National Institutes of Health15, Karolinska Institutet16, Statens Serum Institut17, Lundbeck18, Maastricht University19, Russian Academy20, University of Valencia21, Complutense University of Madrid22, University of Rome Tor Vergata23, Radboud University Nijmegen24, GlaxoSmithKline25, University of Iceland26, Katholieke Universiteit Leuven27, Semmelweis University28, University of Santiago de Compostela29, Cardiff University30, University of Verona31, Broad Institute32, University of California, Los Angeles33
TL;DR: An expanded set of variants in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), and two novel variants showing genome-wide significant association are found.
Abstract: Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10−9] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10−9).
209 citations
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deCODE genetics1, Aarhus University Hospital2, Aarhus University3, University of Oslo4, Copenhagen University Hospital5, University of Iceland6, University of California, Los Angeles7, Utrecht University8, University of Bonn9, University of Helsinki10, Wellcome Trust Sanger Institute11, National Institutes of Health12, Ludwig Maximilian University of Munich13, Glostrup Hospital14, Heidelberg University15, Semmelweis University16, University of Verona17, Radboud University Nijmegen Medical Centre18, Russian Academy19, King's College London20, Sichuan University21, Royal Cornhill Hospital22, Karolinska Institutet23
TL;DR: As it has been proposed that variants such as rs1344706[T]—common and with low relative risk—may also serve to identify regions harboring less common, higher-risk susceptibility alleles, ZNF804A is searched for large copy number variants (CNVs) in psychosis patients and patients with other psychiatric disorders and 39 481 controls.
Abstract: A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).
164 citations
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TL;DR: The CACNA1C rs1006737 polymorphism influences anatomical variation within subcortical regions involved in emotional processing within patients with bipolar disorder and healthy controls.
95 citations
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TL;DR: The hypotheses that the CACNA1C rs1006737 risk allele will modulate neural responses within predefined prefrontal and subcortical regions of interest during emotional face processing and that this effect would be amplified in BD patients were tested.
Abstract: Genome-wide association studies in bipolar disorder (BD)1 have implicated a single-nucleotide polymorphism (rs1006737, G right arrow A) in the CACNA1C gene, which encodes for the alpha 1c (CAV1.2) subunit of the voltage-gated, L-type calcium channel. Neuroimaging studies of healthy individuals report that this risk allele modulates brain function within limbic (amygdala, anterior cingulate gyrus) and hippocampal regions during tasks of reward processing2, 3 and episodic memory. Moreover, animal studies suggest that the CaV1.2 L-type calcium channels influence emotional behaviour through enhanced neurotransmission via the lateral amygdala pathway. On the basis of this evidence, we tested the hypotheses that the CACNA1C rs1006737 risk allele will modulate neural responses within predefined prefrontal and subcortical regions of interest during emotional face processing and that this effect would be amplified in BD patients.
87 citations
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TL;DR: The results suggest that allelic variation in ANK3 impacts cognitive processes associated with signal detection and this mechanism may relate to risk for BD, however, these results require independent replication and confirmation that AnK3 (rs10994336) is a direct functional variant.
Abstract: Background
Abnormalities in cognition have been reported in patients with Bipolar Disorder (BD) and their first degree relatives, suggesting that susceptibility genes for BD may impact on cognitive processes. Recent genome-wide genetic studies have reported a strong association with BD in a single nucleotide polymorphism (SNP) (rs10994336) within ANK3, which codes for Ankyrin 3. This protein is involved in facilitating the propagation of action potentials by regulating the assembly of sodium gated ion channels. Since ANK3 influences the efficiency of transmission of neuronal impulses, allelic variation in this gene may have widespread cognitive effects. Preclinical data suggest that this may principally apply to sequential signal detection, a core process of sustained attention.
47 citations
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TL;DR: Verbal memory and visual learning and memory are moderately heritable, share a genetic overlap with schizophrenia and are valid endophenotypes for the condition.
Abstract: BackgroundVisual and verbal episodic memory deficits are putative endophenotypes for schizophrenia; however, the extent of any genetic overlap of these with schizophrenia is unclear. In this study, we set out to quantify the genetic and environmental contributions to variance in visual and verbal memory performance, and to quantify their genetic relationship with schizophrenia.MethodWe applied bivariate genetic modelling to 280 twins in a classic twin study design, including monozygotic (MZ) and dizygotic (DZ) pairs concordant and discordant for schizophrenia, and healthy control twins. We assessed episodic memory using subtests of the Wechsler Memory Scale – Revised (WMS-R).ResultsGenetic influences (i.e. heritability) contributed significantly to variance in immediate recall of both verbal memory and visual learning, and the delayed recall of verbal and visual memory. Liability to schizophrenia was associated with memory impairment, with evidence of significant phenotypic correlations between all episodic memory measures and schizophrenia. Genetic factors were the main source of the phenotypic correlations for immediate recall of visual learning material; both immediate and delayed recall of verbal memory; and delayed recall of visual memory that, for example, shared genetic variance with schizophrenia, which accounted for 88% of the phenotypic correlation (rph=0.41) between the two.ConclusionsVerbal memory and visual learning and memory are moderately heritable, share a genetic overlap with schizophrenia and are valid endophenotypes for the condition. The inclusion of these endophenotypes in genetic association studies may improve the power to detect susceptibility genes for schizophrenia.
42 citations
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TL;DR: This study does not provide support for the reported association between rs4141463 and autism, and an independent case–control design of 1,170 cases with autism spectrum disorder (ASD) and 35,307 controls is attempted.
Abstract: The Autism Genome Project (AGP) Consortium recently reported genome-wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case-control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non-centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case-control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta-analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944-1.133), with a P-value of 0.5 for ASD and OR of 0.99 (95% CI 0.88-1.11) with P-value = 0.85 for the Autism (A) sub-group. Therefore, this study does not provide support for the reported association between rs4141463 and autism.
38 citations
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TL;DR: A large scale genetic and epidemiological study of Huntington's disease (HD) was carried out in Greece from January 1995 to December 2008 as discussed by the authors, where diagnosis of HD with a CAG expansion ≥ 36 was confirmed in 278 symptomatic individuals.
Abstract: A large scale genetic and epidemiological study of Huntington's disease (HD) was carried out in Greece from January 1995 to December 2008. Diagnostic testing was carried out in 461 symptomatic individuals, while 256 were tested for presymptomatic purposes. The diagnosis of HD with a CAG expansion ≥ 36 was confirmed in 278 symptomatic individuals. The prevalence of HD in Greece was estimated at approximately 2.5 to 5.4:100,000, while the mean minimum incidence was estimated at 2.2 to 4.4 per million per year. The molecular diagnosis of HD was confirmed in the majority of patients (84.4%) sent for confirmation. The false-positive cases 15.6% were characterized by the absence of a family history of HD and the presence of an atypical clinical picture. The uptake of predictive testing for HD was 8.6%. A prenatal test was requested in six pregnancies. The findings of our study do not differ significantly from those of similar studies from other European countries despite the relative genetic isolation of Greece. Of interest is the identification of clusters of HD in Greece. The presence or absence of a family history of HD should be interpreted cautiously, during the diagnostic process.
36 citations
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TL;DR: Replication of association of 3p21.1 with susceptibility to bipolar disorder but not major depression is found, but the association is not strong enough to cause major depression.
Abstract: Replication of association of 3p21.1 with susceptibility to bipolar disorder but not major depression
30 citations