Ravenscraig Hospital

Greenock, United Kingdom

Ravenscraig Hospital

Greenock, United Kingdom
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Steinberg S.,DeCODE Genetics Inc. | De Jong S.,University of California at Los Angeles | Mattheisen M.,Harvard University | Mattheisen M.,University of Bonn | And 169 more authors.
Molecular Psychiatry | Year: 2014

Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255T; odds ratio=1.08; P=6.6 × 10 -11). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255T is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders). © 2014 Macmillan Publishers Limited.


Chen X.,Virginia Commonwealth University | Lee G.,Virginia Commonwealth University | Maher B.S.,Virginia Commonwealth University | Fanous A.H.,Virginia Commonwealth University | And 141 more authors.
Molecular Psychiatry | Year: 2011

We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r 2=0.008; rs10043986-rs4704591, r 2=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10 -4 and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10 -4). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted. © 2011 Macmillan Publishers Limited All rights reserved.


Steinberg S.,DeCODE Genetics Inc. | de Jong S.,University Utrecht | Andreassen O.A.,University of Oslo | Werge T.,Copenhagen University | And 94 more authors.
Human Molecular Genetics | Year: 2011

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). © The Author 2011. Published by Oxford University Press. All rights reserved.


Steinberg S.,DeCODE Genetics Inc. | Mors O.,Aarhus University Hospital | Borglum A.D.,Aarhus University Hospital | Borglum A.D.,University of Aarhus | And 80 more authors.
Molecular Psychiatry | Year: 2011

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 (P5 × 10 8) associated with schizophrenia earlier. However, one variant, rs1344706T, 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 OR1.08, P0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N609, OR1.09, P0.00065). Furthermore, as it has been proposed that variants such as rs1344706Tcommon and with low relative riskmay 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 (P0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P0.0016 for association with the larger set of psychiatric disorders). © 2011 Macmillan Publishers Limited All rights reserved.


Ingason A.,DeCODE Genetics Inc. | Ingason A.,Copenhagen University | Rujescu D.,Ludwig Maximilians University of Munich | Cichon S.,University of Bonn | And 48 more authors.
Molecular Psychiatry | Year: 2011

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 (P0.007) and deletions in 0.12 % of cases and 0.04% of controls (P0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P0.00010) 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. © 2011 Macmillan Publishers Limited All rights reserved.


PubMed | University of Frankfurt am Main, Karolinska Institutet, Semmelweis University, Eli Lilly and Company and 51 more.
Type: Journal Article | Journal: Molecular psychiatry | Year: 2013

Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18206 cases and 42536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22651 additional Icelanders).

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