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M L Hamshere,
J T R Walters,
R Smith,
A L Richards,
E Green,
D Grozeva,
I Jones, L Forty,
L Jones,
K Gordon-Smith, [......],
P Sklar,
S Purcell,
J Kranz,
D Morris,
M Gill,
P Holmans,
N Craddock,
A Corvin,
M J Owen,
M C O'Donovan
Molecular psychiatry 03/2013; · 15.05 Impact Factor
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E K Green,
M Hamshere, L Forty,
K Gordon-Smith,
C Fraser,
E Russell,
D Grozeva,
G Kirov,
P Holmans,
J L Moran,
S Purcell,
P Sklar,
M J Owen,
M C O'Donovan,
L Jones,
I R Jones,
N Craddock
[show abstract]
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ABSTRACT: We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1218 bipolar disorder (BD) cases and 2913 controls that have not been used in any studies previously reported independently or in meta-analyses. The ImmunoChip was designed before the publication of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data. As such 3106 single-nucleotide polymorphisms (SNPs) with a P-value <1 × 10(-3) from the BD meta-analysis by Ferreira et al. were genotyped. We report support for two of the three most strongly associated chromosomal regions in the Ferreira study, CACNA1C (rs1006737, P=4.09 × 10(-4)) and 15q14 (rs2172835, P=0.043) but not ANK3 (rs10994336, P=0.912). We have combined our ImmunoChip data (569 quasi-independent SNPs from the 3016 SNPs genotyped) with the recently published PGC-BD meta-analysis data, using either the PGC-BD combined discovery and replication data where available or just the discovery data where the SNP was not typed in a replication sample in PGC-BD. Our data provide support for two regions, at ODZ4 and CACNA1C, with prior evidence for genome-wide significant (GWS) association in PGC-BD meta-analysis. In addition, the combined analysis shows two novel GWS associations. First, rs7296288 (P=8.97 × 10(-9), odds ratio (OR)=0.9), an intergenic polymorphism on chromosome 12 located between RHEBL1 and DHH. Second, rs3818253 (P=3.88 × 10(-8), OR=1.16), an intronic SNP on chromosome 20q11.2 in the gene TRPC4AP, which lies in a high linkage disequilibrium region along with the genes GSS and MYH7B.Molecular Psychiatry advance online publication, 16 October 2012; doi:10.1038/mp.2012.142.
Molecular psychiatry 10/2012; · 15.05 Impact Factor
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M L Hamshere,
J T R Walters,
R Smith,
A L Richards,
E Green,
D Grozeva,
I Jones, L Forty,
L Jones,
K Gordon-Smith, [......],
P Sklar,
S Purcell,
J Kranz,
D Morris,
M Gill,
P Holmans,
N Craddock,
A Corvin,
M J Owen,
M C O'Donovan
[show abstract]
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ABSTRACT: The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78-100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.Molecular Psychiatry advance online publication, 22 May 2012; doi:10.1038/mp.2012.67.
Molecular psychiatry 05/2012; · 15.05 Impact Factor
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E K Green,
D Grozeva, L Forty,
K Gordon-Smith,
E Russell,
A Farmer,
M Hamshere,
I R Jones,
L Jones,
P McGuffin,
J L Moran,
S Purcell,
P Sklar,
M J Owen,
M C O'Donovan,
N Craddock
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies (GWAS) have identified a number of loci that have strong support for their association with bipolar disorder (BD). The Psychiatric Genome-Wide Association Study (GWAS) Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis of BD GWAS data sets and replication samples identified evidence (P=6.7 × 10(-7), odds ratio (OR)=1.147) of association with the risk of BD at the polymorphism rs9371601 within SYNE1, a gene which encodes nesprin-1. Here we have tested this polymorphism in an independent BD case (n=1527) and control (n=1579) samples, and find evidence for association (P=0.0095) with similar effect sizes to those previously observed in BD (allelic OR=1.148). In a combined (meta) analysis of PGC-BD data (both primary and replication data) and our independent BD samples, we found genome-wide significant evidence for association (P=2.9 × 10(-8), OR=1.104). We have also examined the polymorphism in our recurrent unipolar depression cases (n=1159) and control (n=2592) sample, and found that the risk allele was associated with risk for recurrent major depression (P=0.032, OR=1.118). Our findings add to the evidence that association at this locus influences susceptibility to bipolar and unipolar mood disorders.Molecular Psychiatry advance online publication, 8 May 2012; doi:10.1038/mp.2012.48.
Molecular psychiatry 05/2012; · 15.05 Impact Factor
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E K Green,
D Grozeva,
R Sims,
R Raybould, L Forty,
K Gordon-Smith,
E Russell,
D St Clair,
A H Young,
I N Ferrier,
G Kirov,
I Jones,
L Jones,
M J Owen,
M C O'Donovan,
N Craddock
[show abstract]
[hide abstract]
ABSTRACT: We previously performed a linkage study using families identified through probands meeting criteria for DSM-IV schizoaffective disorder, bipolar type (SABP) and observed a genome-wide significant signal (LOD = 3.54) at chromosome 1q42 close to DISC1. An initial sequencing study of DISC1 using 14 unrelated DSM-IV SABP samples from the linkage study identified 2 non-synonymous coding SNPs in exon 11 in 2 separate individuals. Here we provide evidence of additional rare coding SNPs within exon 11. In sequencing exon 11 in 506 cases and 1,211 controls for variants that occurred only once, 4 additional rare variants were found in cases (P-value = 0.008, Fisher's exact trend test).
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2011; 156B(4):490-2. · 3.70 Impact Factor
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E K Green,
D Grozeva,
I Jones,
L Jones,
G Kirov,
S Caesar,
K Gordon-Smith,
C Fraser, L Forty,
E Russell,
M L Hamshere,
V Moskvina,
I Nikolov,
A Farmer,
P McGuffin,
P A Holmans,
M J Owen,
M C O'Donovan,
N Craddock
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ABSTRACT: Molecular genetic analysis offers opportunities to advance our understanding of the nosological relationship between psychiatric diagnostic categories in general, and the mood and psychotic disorders in particular. Strong evidence (P=7.0 × 10(-7)) of association at the polymorphism rs1006737 (within CACNA1C, the gene encoding the α-1C subunit of the L-type voltage-gated calcium channel) with the risk of bipolar disorder (BD) has recently been reported in a meta-analysis of three genome-wide association studies of BD, including our BD sample (N=1868) studied within the Wellcome Trust Case Control Consortium. Here, we have used our UK case samples of recurrent major depression (N=1196) and schizophrenia (N=479) and UK non-psychiatric comparison groups (N=15316) to examine the spectrum of phenotypic effect of the bipolar risk allele at rs1006737. We found that the risk allele conferred increased risk for schizophrenia (P=0.034) and recurrent major depression (P=0.013) with similar effect sizes to those previously observed in BD (allelic odds ratio ∼1.15). Our findings are evidence of some degree of overlap in the biological underpinnings of susceptibility to mental illness across the clinical spectrum of mood and psychotic disorders, and show that at least some loci can have a relatively general effect on susceptibility to diagnostic categories, as currently defined. Our findings will contribute to a better understanding of the pathogenesis of major psychiatric illness, and such knowledge should be useful in providing an etiological rationale for shaping psychiatric nosology, which is currently reliant entirely on descriptive clinical data.
Molecular psychiatry 08/2009; 15(10):1016-22. · 15.05 Impact Factor
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ABSTRACT: A small but significant proportion of patients with major depressive disorder (MDD) report mild manic symptoms which are below the diagnostic threshold for a hypomanic episode.
We tested for an association between sub-threshold manic symptoms and clinical outcome in almost 600 patients with recurrent MDD who also had no known family history of bipolar disorder.
9.6% of this large sample had a life-time history of sub-threshold manic symptoms. These patients were significantly more likely to have a history of poor response to antidepressants (OR 2.84; 95% CI 1.23-6.56; P < 0.02) and more likely to have experienced psychosis (OR 2.07; 95% CI 1.05-4.09; P < 0.04). They had also experienced more depressive episodes on average (P = 0.006) and were more likely to have been admitted to hospital (P < 0.03).
Sub-threshold manic symptoms in patients with recurrent MDD may be a useful clinical marker for poor response to antidepressants and a more morbid long-term clinical course.
Acta Psychiatrica Scandinavica 12/2008; 119(4):325-9. · 4.22 Impact Factor
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N Craddock,
M. E. Hurles,
N. Cardin,
R. D. Pearson,
V. Plagnol,
S Robson,
D. Vukcevic,
C. Barnes,
D. F. Conrad,
E. Giannoulatou, [......],
J M M Howson,
D Hughes,
S Hunt,
J D Isaacs,
M. Jain,
D P Jewell,
T. Johnson,
J. D. Jolley,
I R Jones,
L. A. Jones et al
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[hide abstract]
ABSTRACT: Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases
